{"gene":"SUMO2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2001,"finding":"SUMO-2 and SUMO-3 contain an internal consensus SUMOylation motif (ψKXE), enabling SAE1/SAE2 (E1) and Ubc9 (E2) to catalyze the formation of polymeric SUMO-2 and SUMO-3 chains on protein substrates in vitro; SUMO-2 chains were also detected in vivo. This chain-forming capacity is not shared by SUMO-1.","method":"In vitro conjugation assay with purified SAE1/SAE2 and Ubc9; in vivo detection of SUMO-2 chains","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified enzymes combined with in vivo confirmation, replicated across subsequent literature","pmids":["11451954"],"is_preprint":false},{"year":2006,"finding":"A SUMO-interacting motif (SIM) was defined that forms a beta-strand binding to the beta2-strand of SUMO2 in parallel or antiparallel orientation; a stretch of acidic/phosphorylated residues flanking the SIM determines specificity for distinct SUMO paralogues including SUMO2 versus SUMO1.","method":"Yeast two-hybrid, bioinformatics, NMR spectroscopy mapping of binding surfaces","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional binding surface mapping, single lab but multiple orthogonal methods","pmids":["16524884"],"is_preprint":false},{"year":2004,"finding":"Crystal structure of truncated human SUMO-2 (residues 9–93) determined at 1.2 Å resolution; the fold (βββαββαβ) is identical to ubiquitin and SUMO-1, but a surface region near the C-terminus shows significantly different charge distribution compared to SUMO-1, which may explain distinct intracellular localizations.","method":"X-ray crystallography (molecular replacement, R3 space group, 1.2 Å resolution)","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with direct structural comparison to SUMO-1","pmids":["15479240"],"is_preprint":false},{"year":2005,"finding":"PIASy, a PIAS-family SUMO E3 ligase, binds mitotic chromosomes, recruits Ubc9, and is specifically required for SUMO-2 conjugation of Topoisomerase-II on mitotic chromosomes in Xenopus egg extracts; PIASy depletion eliminated essentially all chromosomal SUMO-2-conjugated species and blocked anaphase sister chromatid segregation.","method":"Immunodepletion from Xenopus egg extracts, chromatin binding assays, epistasis with PIASy chromatin-binding mutants","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reconstituted Xenopus system with depletion/rescue and mutant analysis, defines E3 ligase-substrate relationship","pmids":["15933717"],"is_preprint":false},{"year":2006,"finding":"SUSP1 (SENP/Ulp family protease) localizes in the nucleoplasm and has strong paralogue bias toward SUMO2/3; it acts preferentially on substrates bearing three or more SUMO2/3 moieties, antagonizing formation of highly conjugated SUMO2/3 species. Depletion of SUSP1 causes redistribution of EGFP-SUMO2/3 into enlarged PML bodies.","method":"Vinyl sulfone inhibitors, model substrate assays, siRNA depletion with fluorescence microscopy of EGFP-SUMO fusions","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical activity assay with specific inhibitors plus cellular imaging, single lab with multiple orthogonal approaches","pmids":["17000875"],"is_preprint":false},{"year":2008,"finding":"Borealin (chromosomal passenger complex component) is preferentially modified by SUMO2/3 during early mitosis. The SUMO E3 ligase RanBP2 interacts with the CPC and stimulates SUMO2/3 modification of Borealin in vitro and in vivo; the SUMO isopeptidase SENP3 specifically binds Borealin and removes SUMO2/3, delineating a mitotic SUMO2/3 conjugation–deconjugation cycle.","method":"Co-immunoprecipitation, in vitro SUMOylation assay, siRNA knockdown, cell synchronization","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution plus reciprocal co-IP and in vivo validation, single lab multiple orthogonal methods","pmids":["18946085"],"is_preprint":false},{"year":2008,"finding":"BMAL1 is predominantly conjugated to poly-SUMO2/3 (not SUMO1) under physiological circadian conditions; this modification localizes BMAL1 to PML nuclear bodies and promotes both its transactivation and ubiquitin-dependent proteasomal degradation. Mutation of the BMAL1 sumoylation site (K259) blocked ubiquitination and proteolysis; covalent SUMO3 attachment restored these effects. SUSP1 (SUMO2/3-specific protease) abolished both sumoylation and ubiquitination of BMAL1.","method":"Site-directed mutagenesis, co-immunoprecipitation, immunofluorescence, proteasome inhibitor treatment, SUSP1 overexpression/knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, mutagenesis, pharmacological and genetic manipulation, multiple orthogonal readouts in single study","pmids":["18644859"],"is_preprint":false},{"year":2010,"finding":"Mass spectrometry identified 103 SUMO-2 acceptor lysines in endogenous target proteins: 76 in canonical ψKxE motifs, 8 in an inverted consensus [ED]xK[VILFP], and 16 in a newly defined hydrophobic cluster SUMOylation motif (HCSM). Cross-talk between SUMOylation and phosphorylation was observed with a preferred spacer of four residues.","method":"Site-specific mass spectrometry proteomics using mutant SUMO-2 with engineered trypsin cleavage site","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct MS identification of modification sites in endogenous proteins at proteome scale, validated on individual substrates","pmids":["20797634"],"is_preprint":false},{"year":2010,"finding":"SENP3, a SUMO2/3-specific protease, is stabilized by low-dose H2O2 (mild oxidative stress), co-localizes with PML bodies, and removes SUMO2/3 from PML; this de-conjugation is responsible for accelerated cell proliferation. Only SUMOylated PML (not a SUMOylation-deficient mutant) inhibits cell proliferation, demonstrating that SUMO2/3 conjugation of PML suppresses proliferation.","method":"siRNA knockdown of SENP3, reconstitution with wild-type vs. SUMOylation-mutant PML, cell proliferation assays, co-localization imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via reconstitution with SUMOylation-deficient mutant, multiple orthogonal approaches, clearly defines mechanism","pmids":["20181954"],"is_preprint":false},{"year":2013,"finding":"PIAS1 is an E3 SUMO ligase for both SUMO-1 and SUMO-2 modification of mutant huntingtin (HTT). SUMO-2 modification of HTT regulates accumulation of insoluble HTT in HeLa cells in a manner mimicking proteasome inhibition; this can be modulated by PIAS1 overexpression and acute knockdown.","method":"Systematic E3 ligase screen, in vitro SUMOylation assays, co-immunoprecipitation, insoluble fraction analysis, PIAS1 knockdown/overexpression","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic screen with follow-up biochemical assays in single lab; E3 identification validated in vitro and in cell","pmids":["23871671"],"is_preprint":false},{"year":2013,"finding":"Cyclin E is dynamically SUMOylated by SUMO2/3 on chromatin during early S phase in a Xenopus cell-free system, independently of Cdk2 activity and origin activation. Cyclin E is the predominant SUMO2/3 target on chromatin in early S phase; SUMO pathway inhibition increased the density of activated replication origins, indicating SUMO2/3-cyclin E conjugation limits replication origin firing.","method":"Xenopus cell-free replication system, immunodepletion, chromatin fractionation, SUMO pathway inhibition","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cell-free reconstitution system with depletion/add-back, direct functional readout (origin firing density), single lab multiple methods","pmids":["23673635"],"is_preprint":false},{"year":2014,"finding":"Proteome-wide identification using SUMO2(T90K) with engineered Lys-C cleavage site revealed >1000 sumoylated lysines in 539 proteins, enabling systematic study of SUMO2 modification sites involved in cell cycle, transcription, and DNA repair.","method":"His6-SUMO2(T90K) expression, Lys-C digestion, diGly remnant immunoprecipitation, mass spectrometry","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — novel engineered method enabling proteome-scale direct identification of SUMO2 acceptor sites, validated by multiple independent analyses","pmids":["24782567"],"is_preprint":false},{"year":2014,"finding":"DBC1 (SIRT1 inhibitor) is specifically modified by SUMO2/3, not SUMO1, in response to DNA damage. ATM/ATR-mediated phosphorylation of DBC1 switches its binding from SENP1 to PIAS3, increasing SUMO2/3 conjugation. SUMOylated DBC1 enhances DBC1-SIRT1 interaction, releasing p53 from SIRT1-mediated repression to enable p53-dependent apoptosis.","method":"Co-immunoprecipitation, siRNA knockdown of PIAS3/SENP1/SUMO2/3, SUMOylation-deficient DBC1 mutant, etoposide treatment, apoptosis assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis via multiple knockdowns and SUMOylation-deficient mutant, identifies upstream kinase signal and downstream effector, multiple orthogonal methods","pmids":["25406032"],"is_preprint":false},{"year":2014,"finding":"SUMO2 is the predominantly expressed SUMO isoform during embryogenesis; Sumo2-null mouse embryos exhibit severe developmental delay and die at ~E10.5, whereas Sumo3-null mice are viable, demonstrating that SUMO2 is essential while SUMO3 is dispensable for embryonic development.","method":"Gene knockout mouse models (Sumo2-/- and Sumo3-/- null mutants), genetic analysis of compound mutants","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function mouse genetics with clear developmental phenotype, compound mutant analysis across multiple litters","pmids":["24891386"],"is_preprint":false},{"year":2015,"finding":"SUMO-2 orchestrates chromatin modifiers in the mammalian DNA damage response (DDR): 20 SUMO-2 conjugates were upregulated and 33 downregulated upon MMS treatment. SUMOylated JARID1B (KDM5B) is ubiquitylated by RNF4 (SUMO-targeted ubiquitin ligase) and degraded by the proteasome; in contrast, JARID1C is recruited to chromatin to demethylate H3K4, demonstrating substrate-specific functional outcomes of SUMO-2 modification in the DDR.","method":"Quantitative SUMO-2 proteomics (SILAC), siRNA knockdown, chromatin fractionation, ubiquitylation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative proteomics combined with functional mechanistic follow-up on specific substrates, single lab multiple orthogonal methods","pmids":["25772364"],"is_preprint":false},{"year":2015,"finding":"Non-native conformers of CFTR NBD1 are recognized by Hsp27, which collaborates with Ubc9 to selectively conjugate SUMO-2 (not other SUMO paralogs) to NBD1 at K447; this SUMO-2 modification leads to RNF4-dependent ubiquitylation and proteasomal degradation. SUMOylation was greater for F508del NBD1 than wild-type in vitro with purified components, and was reduced by stabilizing mutations.","method":"In vitro SUMOylation with purified components, site-directed mutagenesis (K447R), Hsp27 co-immunoprecipitation, intrinsic fluorescence, proteasome assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified components, mutagenesis, conformational studies; single lab multiple orthogonal methods","pmids":["26627832"],"is_preprint":false},{"year":2016,"finding":"ZNF451 isoform 1 (ZNF451-1) functions as a SUMO2/3-specific E3 ligase for PML and selected PML body components in vitro; in vivo, ZNF451-1 RNAi depletion stabilizes PML and increases PML body number, indicating it fine-tunes physiological PML levels cooperatively with RNF4.","method":"In vitro SUMOylation assays, mutational analysis of E3 ligase mechanism, RNAi depletion, PML body quantification by immunofluorescence","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro E3 assay plus cellular RNAi phenotype, single lab, confirms SUMO2/3 specificity","pmids":["27343429"],"is_preprint":false},{"year":2018,"finding":"SUMO2/3 conjugation of PCNA (specifically SUMO2, not SUMO1 or SUMO3) is induced on transcribed chromatin by the RNAPII-bound helicase RECQ5; SUMO2-PCNA enriches histone chaperones CAF1 and FACT via their SUMO-interacting motifs, enhances CAF1-dependent histone deposition, increases repressive chromatin marks at common fragile sites, and dislodges RNAPII to resolve transcription-replication conflicts.","method":"Proteomic analysis of SUMO2-PCNA complexes, SIM-dependent interaction assays, histone deposition assays, ChIP, DSB quantification in RECQ5-deficient cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic identification of SUMO2-PCNA interactors plus functional chromatin and DNA break assays, paralog-specific (SUMO2 vs. SUMO1/3) distinction established","pmids":["30006506"],"is_preprint":false},{"year":2018,"finding":"Acetylation of SUMO2 at lysine K11 is reversible, with SIRT1 acting as the K11 deacetylase. In a purified in vitro system, K11 acetylation impairs SUMO2/3 chain formation and restricts chain length. Mimicking K11 acetylation in cells alters chain architecture by favoring K5- and K35-linked chains while inhibiting K7 and K21 linkages, demonstrating K11 acetylation as a modulator of SUMO2/3 chain topology.","method":"In vitro chain formation assay with acetyl-mimic SUMO2, MS-based SUMO proteomics, SIRT1 deacetylase identification, acetyl-mimic K11Q mutant analysis in cells","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution plus proteomics-based identification of chain linkages, SIRT1 identified as eraser, single lab multiple methods","pmids":["30201799"],"is_preprint":false},{"year":2018,"finding":"Loss of SUMO2/3 (but not SUMO1) results in a spontaneous, potent type I interferon response that is independent of all known IFN-inducing pathways (IRF3 and IRF7 not required), demonstrating that SUMO2 and SUMO3 redundantly and specifically suppress a noncanonical IFN induction mechanism.","method":"Genetic knockout of SUMO2 and SUMO3, IRF3/IRF7 double-knockout epistasis, IFN response measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis across multiple knockout combinations, defines SUMO2/3 pathway specificity versus SUMO1","pmids":["29891701"],"is_preprint":false},{"year":2018,"finding":"DeSUMOylation of MKK7 by the SUMO2/3-specific protease SENP3 promotes MKK7 binding to JNK, enhancing JNK phosphorylation and downstream TLR4 inflammatory signaling in macrophages. ROS-dependent SENP3 accumulation and MKK7 deSUMOylation occur rapidly after LPS stimulation. SENP3 conditional knockout in myeloid cells compromises TLR4 signaling and protects against septic shock.","method":"Conditional SENP3 knockout mice, LPS stimulation assays, JNK phosphorylation measurement, co-immunoprecipitation of MKK7-JNK, in vivo septic shock model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with clean phenotype, co-IP defining substrate-enzyme interaction, mechanistic pathway placement via JNK phosphorylation readout","pmids":["29352108"],"is_preprint":false},{"year":2019,"finding":"SENP6, a poly-SUMO2/3-specific protease, regulates the constitutive centromere-associated network (CCAN) through group de-SUMOylation of >180 interconnected proteins. SENP6 deficiency impairs CENP-T, CENP-W, and CENP-A accumulation at centromeres, causes G2/M accumulation and micronuclei formation. Increased SUMO chains do not lead to proteasomal degradation of CCAN subunits, demonstrating a proteolysis-independent function of SUMO2/3 polymers.","method":"SENP6 knockdown proteomics, cell cycle analysis, immunofluorescence of centromere proteins, proteasome inhibitor experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative proteomics plus functional centromere/cell cycle readouts, proteolysis-independent mechanism established by proteasome inhibition controls","pmids":["31485003"],"is_preprint":false},{"year":2020,"finding":"SENP3-mediated deSUMOylation of IRF8 at K310 (SUMO3 modification) in bone-marrow-derived monocytes promotes osteoclast differentiation by upregulating NFATc1; SENP3 deficiency in BMDMs increases IRF8 SUMO3 modification and suppresses osteoclastogenesis, protecting against ovariectomy-induced bone loss.","method":"Conditional SENP3 knockout mice (myeloid-specific), co-immunoprecipitation, site-specific mutagenesis (K310), ovariectomy bone loss model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mice with defined in vivo bone phenotype, site-specific mutation identifying modification site, mechanistic pathway placement via NFATc1","pmids":["32049023"],"is_preprint":false},{"year":2020,"finding":"Conditional deletion of SUMO2 predominantly in forebrain neurons causes marked impairments in episodic and fear memory and a significant deficit in hippocampal long-term potentiation maintenance, without constitutive changes in gene expression or neuronal morphology, implicating dynamic SUMO2 conjugation in synaptic plasticity.","method":"Conditional Sumo2 knockout mice (forebrain neuron-specific), behavioral cognitive tests, electrophysiology (LTP measurement)","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional neuron-specific KO with LTP electrophysiology and behavioral phenotypes, multiple readouts, excludes morphological/transcriptional explanations","pmids":["32910521"],"is_preprint":false},{"year":2021,"finding":"During oxidative stress, TDP-43 is SUMOylated by SUMO2/3 via the E3 ligase PIAS4 and enriches in cytoplasmic stress granules (SGs); pharmacological inhibition of SUMO2/3-ylation or PIAS4 depletion causes irreversible TDP-43 aggregation. RNA binding to TDP-43 antagonizes PIAS4-mediated SUMO2/3-ylation, while RNA dissociation promotes it, indicating SUMO2/3 conjugation stabilizes cytosolic RNA-free TDP-43 against aggregation.","method":"PIAS4 depletion, pharmacological inhibition, stress granule assembly/disassembly experiments, co-IP, RNA-binding mutant analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — identifies E3 ligase, establishes RNA-dependence of modification, functional rescue with multiple complementary genetic and pharmacological approaches","pmids":["39982984"],"is_preprint":false},{"year":2016,"finding":"SUMO2 activates Calcineurin-NFAT signaling and cardiomyocyte hypertrophy through a direct interaction between SUMO2 and calcineurin A (CnA) that promotes CnA nuclear localization; this effect is sumoylation-independent, as a sumoylation-deficient SUMO2-ΔGG mutant replicates the Cn-NFAT activation and hypertrophic phenotype both in vitro and in vivo.","method":"cDNA library screen, NFAT luciferase reporter assay, sumoylation-deficient mutant (ΔGG), AAV9-mediated in vivo cardiac SUMO2 expression, co-immunoprecipitation of SUMO2-CnA","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV delivery plus in vitro mechanistic assays with sumoylation-deficient mutant, single lab, direct protein interaction identified","pmids":["27767176"],"is_preprint":false},{"year":2014,"finding":"SUMO2 modification of PCNA (via p150 subunit of CAF-1 interaction): the p150 subunit of chromatin assembly factor 1 (CAF-1) interacts directly and preferentially with SUMO2/3 through residues 98-105; p150 depletion causes delocalization of SUMO2/3 from DNA replication foci, and p150 mutants deficient in SUMO2/3 interaction markedly reduce SUMO2/3 at replication foci.","method":"Co-immunoprecipitation, site-directed mutagenesis of p150 (residues 98-105), siRNA knockdown, immunofluorescence at BrdU/PCNA replication foci","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mutagenesis confirming binding region plus functional localization readout; published 2009, single lab","pmids":["19919826"],"is_preprint":false},{"year":2022,"finding":"Crystal structure of the SENP7 catalytic domain bound to SUMO2 reveals that a unique Loop1 insertion in SENP7 makes specific contacts with SUMO2 that are absent in other SENP family members, establishing the structural basis for SENP6/7's SUMO2/3 isoform preference and poly-SUMO2 chain dismantling activity.","method":"X-ray crystallography of SENP7-SUMO2 complex, structure-function comparison with SENP2-Loop1 chimera","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation using Loop1 chimera, defines isoform specificity determinants","pmids":["36334780"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of SENP2-Loop1 chimera (containing the SENP6/7 Loop1 insertion) in complex with SUMO2 at 2.15 Å shows unique interface contacts exclusive to SENP6/7; the Loop1 chimera displays enhanced proteolytic activity toward diSUMO2 and polySUMO2 substrates, confirming Loop1 as determinant for SUMO2/3 activity and specificity.","method":"X-ray crystallography of chimeric SENP2-Loop1/SUMO2 complex, in vitro protease activity assays with diSUMO2 and polySUMO2 substrates","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with functional enzymatic assays, single lab, directly links structural feature to substrate specificity","pmids":["24424631"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of SENP1 catalytic domain in noncovalent complex with SUMO2 at 2.62 Å resolution shows that complex formation is driven by polar interactions and limited hydrophobic contacts; the SUMO2 C-terminal QQTGG motif protrudes into the SENP1 catalytic triad, providing the structural basis for SUMO2 maturation and deSUMOylation.","method":"X-ray crystallography of SENP1-SUMO2 noncovalent complex","journal":"Acta crystallographica. Section F, Structural biology communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure without extensive functional mutagenesis validation, single paper","pmids":["31045562"],"is_preprint":false},{"year":2008,"finding":"SMT3IP1 (nucleolar SUMO-specific protease) preferentially removes SUMO-2 from nucleophosmin (NPM) in both nucleolar and cytoplasmic compartments; catalytically inactive SMT3IP1 mutant increases SUMO-2-modified NPM in a dominant-negative manner; SUMO-2 conjugation of cytoplasmic mutant NPM is markedly elevated in an ARF-dependent manner.","method":"Yeast two-hybrid identification of NPM as SMT3IP1 substrate, dominant-negative catalytic mutant, ARF-dependent SUMOylation analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid substrate identification with dominant-negative protease mutant validation, single lab","pmids":["18639523"],"is_preprint":false},{"year":2018,"finding":"ATF5 is modified by SUMO2/3 at a conserved consensus site; SUMOylation of ATF5 is elevated in G1 phase and diminished in G2/M phase. SUMO2/3 modification disrupts ATF5 interaction with centrosomal proteins, dislodging ATF5 from the centrosome at end of M phase. Blockade of ATF5 SUMOylation deregulates the centrosome cycle, impedes ATF5 translocation, and causes genomic instability and G2/M arrest.","method":"Cell cycle synchronization, co-immunoprecipitation with centrosomal proteins, SUMOylation-deficient mutant, genomic instability assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-cycle-resolved modification plus functional mutant phenotype, single lab, multiple readouts","pmids":["29326161"],"is_preprint":false},{"year":2019,"finding":"SUMOylation of polyQ-ataxin-7 (polyQ-ATXN7) by SUMO2/3 recruits the SUMO-targeted ubiquitin ligase RNF4; overexpression of RNF4 and/or SUMO2 significantly decreases polyQ-ATXN7 levels and increases its polyubiquitination upon proteasome inhibition, demonstrating a SUMO2-dependent degradation pathway for misfolded ataxin-7.","method":"Co-immunoprecipitation, immunofluorescence, proximity ligation assay, RNF4/SUMO2 overexpression, SCA7 knockin mouse model analysis","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and overexpression with polyubiquitination assay, validated in mouse model, single lab","pmids":["30559154"],"is_preprint":false},{"year":2025,"finding":"Ferroptosis induces lactylation of SUMO2 at K11 (SUMO2-K11la); this modification impairs the interaction between SUMO2 and ACSL4, facilitating ACSL4 degradation, disrupting lipid metabolism, and mitigating ferroptosis in lung adenocarcinoma. AARS1 is the lactyltransferase and HDAC1 is the delactylase for SUMO2-K11la.","method":"SUMOylation proteomics, co-IP assays, metabolomic profiling, identification of AARS1 as lactyltransferase and HDAC1 as delactylase, cell-penetrating peptide inhibitor, xenograft models","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus co-IP and functional assays identifying writer/eraser, in vivo xenograft validation, single lab","pmids":["41057295"],"is_preprint":false},{"year":2014,"finding":"SUMO2 interacts with and promotes cap-dependent mRNA translation by enhancing the interaction between eIF4E and eIF4G to form the active eIF4F complex; SUMO2 overexpression partially reverses the effect of 4EGI-1 (eIF4E/eIF4G interaction inhibitor), while SUMO2 knockdown impairs cap-dependent translation and promotes apoptosis.","method":"Co-immunoprecipitation of eIF4E-eIF4G, SUMO2 overexpression/shRNA knockdown, 4EGI-1 rescue assay, polysome profiling","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with partial mechanistic follow-up, single lab, not independently replicated","pmids":["24971752"],"is_preprint":false},{"year":2001,"finding":"SMRZ (striated muscle RING zinc finger protein) interacts with SMT3b (SUMO2) through its RING domain; this interaction is abolished by mutagenesis of conserved RING domain residues, and SMRZ localizes to the nucleus in muscle cells.","method":"Co-immunoprecipitation, RING domain mutagenesis, transient transfection with nuclear localization imaging","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP with mutagenesis, single lab, no functional downstream consequence established for SUMO2 itself","pmids":["11283016"],"is_preprint":false},{"year":2012,"finding":"ARHGAP21 (a RhoGAP modulating cell migration via Cdc42 and FAK) is specifically modified by SUMO2/3 at lysine K1443; SUMO2/3-modified ARHGAP21 co-localizes with SUMO2/3 in cytoplasm and membrane compartments, and its SUMOylation may be related to cell proliferation.","method":"Mass spectrometry identification of modified form, co-immunoprecipitation, in vitro SUMOylation, immunofluorescence","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vitro SUMOylation plus co-IP, site mapped, but functional consequence only suggested, single lab","pmids":["22922005"],"is_preprint":false},{"year":2022,"finding":"γ-actin is SUMOylated by SUMO2 at K68 and K284 in cardiomyocytes; SUMOylation promotes nuclear deposition of γ-actin and DNA damage repair. SUMO2 silencing decreased nuclear γ-actin and exacerbated DNA damage; K68R/K284R double mutant γ-actin failed to protect cardiomyocytes against hypoxia-reoxygenation challenge.","method":"Strep-SUMO2 affinity purification with MALDI-TOF-MS identification, site-directed mutagenesis (K68R/K284R), in vivo myocardial infarction model, H9c2 hypoxia-reoxygenation model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identified by purification/MS, mutagenesis of acceptor lysines, functional readout in multiple models, single lab","pmids":["35864967"],"is_preprint":false}],"current_model":"SUMO2 forms polymeric chains (via its internal ψKXE motif) using the SAE1/SAE2 E1 and Ubc9 E2 conjugating machinery; it is conjugated to hundreds of nuclear substrates—especially under stress conditions—by E3 ligases including PIASy, RanBP2, ZNF451-1, and PIAS4, and is removed by SUMO2/3-specific proteases (SENP3, SENP6, SENP7, SUSP1) to regulate protein stability (via the STUbL/RNF4-proteasome axis), DNA replication origin firing, mitotic chromosome segregation, DNA damage responses, circadian timing, type I interferon suppression, synaptic plasticity, and embryonic development."},"narrative":{"mechanistic_narrative":"SUMO2 is a small ubiquitin-like modifier that, unlike SUMO1, carries an internal ψKxE consensus motif allowing it to be polymerized into SUMO2/3 chains by the SAE1/SAE2 E1 and Ubc9 E2 machinery, building a dynamic conjugation system that decorates hundreds of predominantly nuclear substrates [PMID:11451954, PMID:20797634, PMID:24782567]. Substrate-selective conjugation is directed by distinct E3 ligases—PIASy on mitotic chromosomes, RanBP2 within the chromosomal passenger complex, PIAS3 in the DNA damage response, PIAS4 on stress-granule TDP-43, and ZNF451-1 at PML bodies—and is read out by SUMO-interacting-motif (SIM) proteins whose acidic/phosphorylated flanks tune paralog selectivity [PMID:16524884, PMID:15933717, PMID:18946085, PMID:25406032, PMID:27343429, PMID:39982984]. A major functional output is coupling to protein turnover: SUMO2 chains recruit the STUbL RNF4 to drive proteasomal degradation of substrates such as JARID1B, CFTR NBD1, and misfolded polyQ proteins [PMID:25772364, PMID:26627832, PMID:30559154]. Through these conjugation–deconjugation cycles SUMO2 governs mitotic chromosome segregation and centromere assembly, restrains DNA replication origin firing via cyclin E, orchestrates chromatin modifiers in the DNA damage response, controls circadian BMAL1 turnover, and suppresses a noncanonical type I interferon response redundantly with SUMO3 [PMID:15933717, PMID:18644859, PMID:23673635, PMID:25772364, PMID:29891701, PMID:31485003]. Removal of SUMO2/3 is carried out by isoform-selective SENP/Ulp proteases (SENP3, SENP6, SENP7, SUSP1), whose structures reveal a SENP6/7 Loop1 insertion that confers poly-SUMO2 chain specificity and whose deconjugation activity feeds into proliferation, centromere maintenance, and inflammatory and osteoclast signaling [PMID:17000875, PMID:20181954, PMID:31485003, PMID:36334780, PMID:24424631, PMID:29352108, PMID:32049023]. SUMO2 is the essential, predominant embryonic SUMO isoform—Sumo2-null mice die at ~E10.5 while Sumo3-null mice are viable—and conditional neuronal loss impairs hippocampal LTP and memory, establishing physiological roles in development and synaptic plasticity [PMID:24891386, PMID:32910521].","teleology":[{"year":2001,"claim":"Established the defining biochemical property distinguishing SUMO2 from SUMO1—its capacity to form polymeric chains—answering how a single modifier could generate higher-order signals.","evidence":"In vitro conjugation with purified SAE1/SAE2 and Ubc9 plus in vivo chain detection","pmids":["11451954"],"confidence":"High","gaps":["Did not define which E3 ligases catalyze chain formation in vivo","Did not establish functional consequences of chains"]},{"year":2004,"claim":"Resolved the SUMO2 fold and identified C-terminal surface charge differences from SUMO1 as a structural basis for paralog-specific behavior.","evidence":"X-ray crystallography of human SUMO-2 at 1.2 Å with comparison to SUMO-1","pmids":["15479240"],"confidence":"High","gaps":["Structural correlate of distinct localization inferred, not demonstrated","No bound partner in the structure"]},{"year":2006,"claim":"Defined how SUMO2 is recognized non-covalently, showing a SIM beta-strand engages SUMO2 with flanking acidic/phosphorylated residues encoding paralog selectivity.","evidence":"Yeast two-hybrid, bioinformatics and NMR mapping of SIM-SUMO2 interface","pmids":["16524884"],"confidence":"High","gaps":["Selectivity rules derived from limited SIM set","In vivo functional impact of paralog discrimination not tested"]},{"year":2005,"claim":"Connected SUMO2 chains to a specific cellular process by identifying PIASy as the E3 driving Topoisomerase-II SUMO2 conjugation required for sister chromatid segregation.","evidence":"Immunodepletion and chromatin assays in Xenopus egg extracts with PIASy mutants","pmids":["15933717"],"confidence":"High","gaps":["Mechanism by which SUMO2-TopoII enables segregation not fully resolved","Mammalian validation not in this study"]},{"year":2008,"claim":"Demonstrated a complete mitotic SUMO2/3 conjugation-deconjugation cycle on Borealin, defining RanBP2 as writer and SENP3 as eraser for a CPC substrate.","evidence":"Co-IP, in vitro SUMOylation, siRNA and cell synchronization","pmids":["18946085"],"confidence":"High","gaps":["Functional consequence of Borealin SUMO2/3 cycling for CPC activity not fully defined"]},{"year":2008,"claim":"Linked SUMO2/3 to circadian timing and to coupled degradation, showing poly-SUMO2/3 of BMAL1 promotes transactivation and proteasomal turnover at PML bodies.","evidence":"Site-directed mutagenesis (K259), co-IP, proteasome inhibition, SUSP1 manipulation","pmids":["18644859"],"confidence":"High","gaps":["Identity of the BMAL1 E3 ligase not established","Ubiquitin ligase coupling SUMO to degradation not named here"]},{"year":2006,"claim":"Identified a SUMO2/3-selective protease (SUSP1) acting on poly-SUMO2/3 substrates, establishing chain-length-selective deconjugation and PML-body homeostasis.","evidence":"Vinyl sulfone inhibitors, model substrate assays, siRNA and EGFP-SUMO imaging","pmids":["17000875"],"confidence":"High","gaps":["Endogenous physiological substrates not defined","Mechanism of chain-length preference structurally unexplained at the time"]},{"year":2010,"claim":"Defined the SUMO2 acceptor-site code and phospho-cross-talk through proteome-scale site mapping, revealing canonical and non-canonical motifs.","evidence":"Site-specific MS proteomics using engineered trypsin-cleavable SUMO-2","pmids":["20797634"],"confidence":"High","gaps":["Functional importance of each site not tested","HCSM and inverted-motif recognition determinants unknown"]},{"year":2010,"claim":"Tied SENP3-driven SUMO2/3 removal from PML to proliferation control under oxidative stress, showing SUMOylated PML is antiproliferative.","evidence":"SENP3 siRNA, reconstitution with SUMO-deficient PML, proliferation and colocalization assays","pmids":["20181954"],"confidence":"High","gaps":["Downstream proliferative effectors of PML deSUMOylation not delineated"]},{"year":2013,"claim":"Established a SUMO2/3 brake on DNA replication by showing cyclin E is the predominant chromatin SUMO2/3 target limiting origin firing in early S phase.","evidence":"Xenopus cell-free replication, immunodepletion, chromatin fractionation, SUMO inhibition","pmids":["23673635"],"confidence":"High","gaps":["E3 ligase for chromatin cyclin E SUMO2/3 not identified","Molecular link from cyclin E SUMOylation to origin licensing unresolved"]},{"year":2013,"claim":"Implicated SUMO2 in proteostasis of disease aggregates, identifying PIAS1 as an E3 modulating mutant huntingtin solubility.","evidence":"E3 ligase screen, in vitro SUMOylation, insoluble fraction analysis, PIAS1 manipulation","pmids":["23871671"],"confidence":"Medium","gaps":["Single-lab screen without reciprocal in vivo validation","Direct link to clearance machinery not resolved"]},{"year":2014,"claim":"Scaled SUMO2 site mapping to >1000 lysines, enabling systematic dissection of cell cycle, transcription and DNA repair substrates.","evidence":"His6-SUMO2(T90K) with Lys-C diGly remnant IP and MS","pmids":["24782567"],"confidence":"High","gaps":["Functional consequences of most sites untested","E3/protease assignments per-site not made"]},{"year":2014,"claim":"Showed SUMO2/3 conjugation acts as a phospho-gated apoptotic switch on DBC1, with ATM/ATR phosphorylation steering DBC1 from SENP1 to PIAS3 to release p53.","evidence":"Co-IP, PIAS3/SENP1/SUMO2/3 knockdowns, SUMO-deficient DBC1 mutant, etoposide and apoptosis assays","pmids":["25406032"],"confidence":"High","gaps":["Structural basis of the phospho-switch in ligase/protease choice not defined"]},{"year":2014,"claim":"Linked SUMO2/3 to replication-coupled chromatin assembly via direct CAF-1 p150 SIM binding that recruits SUMO2/3 to replication foci.","evidence":"Co-IP, p150 residue 98-105 mutagenesis, siRNA, replication-foci immunofluorescence","pmids":["19919826"],"confidence":"Medium","gaps":["Identity of the SUMO2/3-modified target at foci not pinned down here","Single-lab finding"]},{"year":2015,"claim":"Defined substrate-specific SUMO2 outcomes in the DDR—degradation of JARID1B via RNF4 versus chromatin recruitment of JARID1C—showing SUMO can route substrates to opposite fates.","evidence":"Quantitative SILAC SUMO-2 proteomics, siRNA, chromatin fractionation, ubiquitylation assays","pmids":["25772364"],"confidence":"High","gaps":["Determinants selecting degradation versus recruitment unclear"]},{"year":2015,"claim":"Connected SUMO2 to conformational quality control, showing Hsp27/Ubc9 conjugate SUMO2 to misfolded CFTR NBD1 for RNF4-dependent degradation.","evidence":"In vitro SUMOylation with purified components, K447R mutagenesis, Hsp27 co-IP, proteasome assays","pmids":["26627832"],"confidence":"High","gaps":["How Hsp27 selects SUMO2 over other paralogs mechanistically unresolved","In-cell relevance for F508del trafficking not fully established"]},{"year":2016,"claim":"Added ZNF451-1 as a SUMO2/3-specific E3 that fine-tunes PML levels cooperatively with RNF4.","evidence":"In vitro SUMOylation, E3 mechanism mutants, RNAi and PML body quantification","pmids":["27343429"],"confidence":"Medium","gaps":["Single-lab; in vivo physiological role of ZNF451-1 not established"]},{"year":2016,"claim":"Revealed a non-conjugative SUMO2 function, showing SUMO2 directly binds calcineurin A to drive its nuclear localization and cardiac hypertrophy independent of conjugation.","evidence":"cDNA screen, NFAT reporter, SUMO2-ΔGG mutant, AAV9 in vivo cardiac expression, co-IP","pmids":["27767176"],"confidence":"Medium","gaps":["Single-lab; structural basis of the conjugation-independent interaction not defined"]},{"year":2018,"claim":"Established the structural and regulatory features of SUMO2 chains, defining K11 acetylation (erased by SIRT1) as a topology modulator restricting chain length and shifting linkage usage.","evidence":"In vitro chain assays with acetyl-mimic SUMO2, MS chain-linkage proteomics, SIRT1 identification","pmids":["30201799"],"confidence":"High","gaps":["Writer of SUMO2 K11 acetylation not identified","Physiological contexts of acetylation-controlled topology untested"]},{"year":2018,"claim":"Identified a paralog-specific SUMO2-PCNA signal generated by RECQ5 that recruits CAF1/FACT to resolve transcription-replication conflicts.","evidence":"Proteomics of SUMO2-PCNA complexes, SIM-dependent interaction and histone deposition assays, ChIP, DSB quantification","pmids":["30006506"],"confidence":"High","gaps":["E3 ligase generating SUMO2-PCNA on transcribed chromatin not named","Why SUMO2 but not SUMO3 is selected unresolved"]},{"year":2018,"claim":"Demonstrated redundant, paralog-specific suppression of innate immunity, with SUMO2/3 loss triggering a noncanonical IFN response independent of IRF3/IRF7.","evidence":"SUMO2/SUMO3 knockouts and IRF3/IRF7 double-knockout epistasis with IFN readouts","pmids":["29891701"],"confidence":"High","gaps":["The noncanonical IFN-inducing sensor/pathway not identified","Relevant SUMO2/3 substrates suppressing IFN unknown"]},{"year":2018,"claim":"Placed SUMO2/3 deconjugation within inflammatory signaling, showing SENP3-mediated MKK7 deSUMOylation enhances JNK/TLR4 signaling in macrophages.","evidence":"Conditional SENP3 KO mice, LPS assays, JNK phosphorylation, MKK7-JNK co-IP, septic shock model","pmids":["29352108"],"confidence":"High","gaps":["MKK7 SUMO acceptor site and writer E3 not defined here"]},{"year":2018,"claim":"Linked SUMO2/3 to centrosome-cycle control via cell-cycle-resolved ATF5 SUMOylation that dislodges ATF5 from the centrosome.","evidence":"Cell synchronization, centrosomal co-IP, SUMO-deficient ATF5 mutant, genomic instability assays","pmids":["29326161"],"confidence":"Medium","gaps":["Single-lab; E3/protease controlling ATF5 cycling not identified"]},{"year":2014,"claim":"Proposed a cytoplasmic, non-degradative SUMO2 role in cap-dependent translation by promoting eIF4E-eIF4G assembly.","evidence":"eIF4E-eIF4G co-IP, SUMO2 overexpression/knockdown, 4EGI-1 rescue, polysome profiling","pmids":["24971752"],"confidence":"Low","gaps":["Single Co-IP with partial follow-up, not independently replicated","Whether SUMO2 acts via conjugation unclear"]},{"year":2019,"claim":"Defined a proteolysis-independent role for SUMO2/3 chains in centromere assembly, with SENP6 group-deSUMOylating the CCAN to maintain CENP loading.","evidence":"SENP6 knockdown proteomics, cell cycle analysis, centromere immunofluorescence, proteasome inhibitor controls","pmids":["31485003"],"confidence":"High","gaps":["How SUMO chains stabilize CCAN without triggering degradation mechanistically unclear"]},{"year":2019,"claim":"Extended SUMO2-RNF4 clearance to neurodegenerative aggregates, showing SUMO2/3-RNF4 promotes polyQ-ataxin-7 degradation.","evidence":"Co-IP, PLA, RNF4/SUMO2 overexpression, SCA7 knockin mouse","pmids":["30559154"],"confidence":"Medium","gaps":["E3 SUMO ligase for ATXN7 not identified","Therapeutic relevance untested"]},{"year":2019,"claim":"Provided the structural basis for SUMO2 maturation/deconjugation by SENP1 via the C-terminal QQTGG motif engaging the catalytic triad.","evidence":"X-ray crystallography of SENP1-SUMO2 noncovalent complex at 2.62 Å","pmids":["31045562"],"confidence":"Medium","gaps":["No functional mutagenesis validation in this study"]},{"year":2020,"claim":"Established a physiological osteoclast role for SUMO2/3 deconjugation, with SENP3 removing SUMO3 from IRF8 to permit NFATc1-driven osteoclastogenesis.","evidence":"Myeloid-specific SENP3 KO mice, co-IP, K310 mutagenesis, ovariectomy bone-loss model","pmids":["32049023"],"confidence":"High","gaps":["Writer E3 for IRF8 SUMO3 not defined","Mechanism by which IRF8 SUMOylation limits NFATc1 not detailed"]},{"year":2020,"claim":"Demonstrated SUMO2's physiological requirement in the nervous system, with conditional neuronal loss impairing LTP and memory absent transcriptional/morphological changes.","evidence":"Forebrain-specific Sumo2 KO mice, behavioral tests, LTP electrophysiology","pmids":["32910521"],"confidence":"High","gaps":["Synaptic SUMO2 substrates mediating plasticity not identified"]},{"year":2022,"claim":"Provided the definitive structural explanation for SENP6/7 poly-SUMO2 specificity via a unique Loop1 insertion contacting SUMO2.","evidence":"Crystal structure of SENP7-SUMO2 with SENP2-Loop1 chimera comparison","pmids":["36334780"],"confidence":"High","gaps":["Chain-disassembly processivity mechanism not fully resolved"]},{"year":2022,"claim":"Identified γ-actin as a cardioprotective SUMO2 substrate whose modification at K68/K284 promotes nuclear deposition and DNA-damage repair.","evidence":"Strep-SUMO2 affinity MS, K68R/K284R mutagenesis, MI and hypoxia-reoxygenation models","pmids":["35864967"],"confidence":"Medium","gaps":["E3/protease for γ-actin SUMO2 not identified","Single-lab finding"]},{"year":2025,"claim":"Revealed metabolic regulation of SUMO2 itself, with ferroptosis-induced K11 lactylation impairing SUMO2-ACSL4 interaction to remodel lipid metabolism.","evidence":"SUMOylation proteomics, co-IP, metabolomics, AARS1/HDAC1 writer-eraser identification, xenografts","pmids":["41057295"],"confidence":"Medium","gaps":["Interplay of K11 lactylation with K11 acetylation not reconciled","Single-lab finding"]},{"year":null,"claim":"The sensor and substrates underlying SUMO2/3-mediated suppression of noncanonical type I interferon, and the determinants that route a SUMO2-modified substrate toward degradation, recruitment, or non-degradative stabilization, remain unresolved.","evidence":"Open question synthesized across DDR, immune, and proteostasis findings","pmids":[],"confidence":"Low","gaps":["No identified IFN-inducing sensor for SUMO2/3 loss","No general rule predicting SUMO2-driven substrate fate","E3 assignments missing for many physiological substrates"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0031386","term_label":"protein tag activity","supporting_discovery_ids":[0,7,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,12,14,25]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,7,11]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[30]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3,10,21]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[24,36]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,5,10,21,31]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[12,14,17]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[14,17,26]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[14,15,32]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[19,20,22]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[6]}],"complexes":["PML nuclear body","constitutive centromere-associated network (CCAN)","chromosomal passenger complex"],"partners":["UBE2I","PIAS4","RNF4","SENP3","SENP6","SENP7","PCNA","BMAL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P61956","full_name":"Small ubiquitin-related modifier 2","aliases":["HSMT3","SMT3 homolog 2","SUMO-3","Sentrin-2","Ubiquitin-like protein SMT3B","Smt3B"],"length_aa":95,"mass_kda":10.9,"function":"Ubiquitin-like protein that can be covalently attached to proteins as a monomer or as a lysine-linked polymer. Covalent attachment via an isopeptide bond to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I, and can be promoted by an E3 ligase such as PIAS1-4, RANBP2, CBX4 or ZNF451 (PubMed:26524494). This post-translational modification on lysine residues of proteins plays a crucial role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Polymeric SUMO2 chains are also susceptible to polyubiquitination which functions as a signal for proteasomal degradation of modified proteins (PubMed:18408734, PubMed:18538659, PubMed:21965678, PubMed:9556629). Plays a role in the regulation of sumoylation status of SETX (PubMed:24105744)","subcellular_location":"Nucleus; Nucleus, PML body","url":"https://www.uniprot.org/uniprotkb/P61956/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SUMO2","classification":"Common Essential","n_dependent_lines":259,"n_total_lines":317,"dependency_fraction":0.8170347003154574},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SUMO2","total_profiled":1310},"omim":[{"mim_id":"620480","title":"TRIPARTITE MOTIF FAMILY-LIKE PROTEIN 2; TRIML2","url":"https://www.omim.org/entry/620480"},{"mim_id":"617842","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 1; PSMD1","url":"https://www.omim.org/entry/617842"},{"mim_id":"617470","title":"UBIQUITIN-SPECIFIC PEPTIDASE-LIKE 1; USPL1","url":"https://www.omim.org/entry/617470"},{"mim_id":"615708","title":"ZINC FINGER PROTEIN 451; ZNF451","url":"https://www.omim.org/entry/615708"},{"mim_id":"614637","title":"DESUMOYLATING ISOPEPTIDASE 1; DESI1","url":"https://www.omim.org/entry/614637"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Calyx","reliability":"Additional"},{"location":"Connecting piece","reliability":"Additional"},{"location":"Flagellar centriole","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SUMO2"},"hgnc":{"alias_symbol":["SMT3B"],"prev_symbol":["SMT3H2"]},"alphafold":{"accession":"P61956","domains":[{"cath_id":"3.10.20.90","chopping":"16-87","consensus_level":"high","plddt":91.9757,"start":16,"end":87}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61956","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61956-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61956-F1-predicted_aligned_error_v6.png","plddt_mean":83.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SUMO2","jax_strain_url":"https://www.jax.org/strain/search?query=SUMO2"},"sequence":{"accession":"P61956","fasta_url":"https://rest.uniprot.org/uniprotkb/P61956.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61956/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61956"}},"corpus_meta":[{"pmid":"11451954","id":"PMC_11451954","title":"Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11451954","citation_count":697,"is_preprint":false},{"pmid":"16524884","id":"PMC_16524884","title":"Specification of SUMO1- and SUMO2-interacting motifs.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16524884","citation_count":441,"is_preprint":false},{"pmid":"20797634","id":"PMC_20797634","title":"Site-specific identification of SUMO-2 targets in cells reveals an inverted SUMOylation motif and a hydrophobic cluster SUMOylation motif.","date":"2010","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/20797634","citation_count":270,"is_preprint":false},{"pmid":"17000644","id":"PMC_17000644","title":"Distinct and overlapping sets of SUMO-1 and SUMO-2 target proteins revealed by quantitative proteomics.","date":"2006","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/17000644","citation_count":254,"is_preprint":false},{"pmid":"15175327","id":"PMC_15175327","title":"A proteomic study of SUMO-2 target proteins.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15175327","citation_count":183,"is_preprint":false},{"pmid":"24782567","id":"PMC_24782567","title":"Proteome-wide identification of SUMO2 modification sites.","date":"2014","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/24782567","citation_count":177,"is_preprint":false},{"pmid":"24891386","id":"PMC_24891386","title":"SUMO2 is essential while SUMO3 is dispensable for mouse embryonic development.","date":"2014","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/24891386","citation_count":161,"is_preprint":false},{"pmid":"18644859","id":"PMC_18644859","title":"Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18644859","citation_count":138,"is_preprint":false},{"pmid":"17000875","id":"PMC_17000875","title":"SUSP1 antagonizes formation of highly SUMO2/3-conjugated species.","date":"2006","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17000875","citation_count":129,"is_preprint":false},{"pmid":"19033381","id":"PMC_19033381","title":"Loss of SUMO1 in mice affects RanGAP1 localization and formation of PML nuclear bodies, but is not lethal as it can be compensated by SUMO2 or SUMO3.","date":"2008","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/19033381","citation_count":127,"is_preprint":false},{"pmid":"15933717","id":"PMC_15933717","title":"PIASy mediates SUMO-2 conjugation of Topoisomerase-II on mitotic chromosomes.","date":"2005","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/15933717","citation_count":123,"is_preprint":false},{"pmid":"34465340","id":"PMC_34465340","title":"Circular RNA circRNF13 inhibits proliferation and metastasis of nasopharyngeal carcinoma via SUMO2.","date":"2021","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34465340","citation_count":116,"is_preprint":false},{"pmid":"25772364","id":"PMC_25772364","title":"SUMO-2 Orchestrates Chromatin Modifiers in Response to DNA Damage.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25772364","citation_count":112,"is_preprint":false},{"pmid":"18946085","id":"PMC_18946085","title":"RanBP2 and SENP3 function in a mitotic SUMO2/3 conjugation-deconjugation cycle on Borealin.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18946085","citation_count":97,"is_preprint":false},{"pmid":"23871671","id":"PMC_23871671","title":"SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/23871671","citation_count":96,"is_preprint":false},{"pmid":"16567619","id":"PMC_16567619","title":"NXP-2 association with SUMO-2 depends on lysines required for transcriptional repression.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16567619","citation_count":95,"is_preprint":false},{"pmid":"20181954","id":"PMC_20181954","title":"SENP3-mediated de-conjugation of SUMO2/3 from promyelocytic leukemia is correlated with accelerated cell proliferation under mild oxidative stress.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20181954","citation_count":92,"is_preprint":false},{"pmid":"12810706","id":"PMC_12810706","title":"Modification of CCAAT/enhancer-binding protein-beta by the small ubiquitin-like modifier (SUMO) family members, SUMO-2 and SUMO-3.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12810706","citation_count":74,"is_preprint":false},{"pmid":"19240082","id":"PMC_19240082","title":"Novel proteomics strategy brings insight into the prevalence of SUMO-2 target sites.","date":"2009","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/19240082","citation_count":74,"is_preprint":false},{"pmid":"24651501","id":"PMC_24651501","title":"Identification and analysis of endogenous SUMO1 and SUMO2/3 targets in mammalian cells and tissues using monoclonal antibodies.","date":"2014","source":"Nature protocols","url":"https://pubmed.ncbi.nlm.nih.gov/24651501","citation_count":65,"is_preprint":false},{"pmid":"26200910","id":"PMC_26200910","title":"Analysis of the SUMO2 Proteome during HSV-1 Infection.","date":"2015","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/26200910","citation_count":64,"is_preprint":false},{"pmid":"15479240","id":"PMC_15479240","title":"Crystal structures of the human SUMO-2 protein at 1.6 A and 1.2 A resolution: implication on the functional differences of SUMO proteins.","date":"2004","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15479240","citation_count":64,"is_preprint":false},{"pmid":"31485003","id":"PMC_31485003","title":"The poly-SUMO2/3 protease SENP6 enables assembly of the constitutive centromere-associated network by group deSUMOylation.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31485003","citation_count":62,"is_preprint":false},{"pmid":"21898723","id":"PMC_21898723","title":"Expanded click conjugation of recombinant proteins with ubiquitin-like modifiers reveals altered substrate preference of SUMO2-modified Ubc9.","date":"2011","source":"Angewandte Chemie (International ed. in English)","url":"https://pubmed.ncbi.nlm.nih.gov/21898723","citation_count":57,"is_preprint":false},{"pmid":"25244549","id":"PMC_25244549","title":"Traceless preparation of C-terminal α-ketoacids for chemical protein synthesis by α-ketoacid-hydroxylamine ligation: synthesis of SUMO2/3.","date":"2014","source":"Angewandte Chemie (International ed. in English)","url":"https://pubmed.ncbi.nlm.nih.gov/25244549","citation_count":53,"is_preprint":false},{"pmid":"30006506","id":"PMC_30006506","title":"SUMO2 conjugation of PCNA facilitates chromatin remodeling to resolve transcription-replication conflicts.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30006506","citation_count":50,"is_preprint":false},{"pmid":"26947976","id":"PMC_26947976","title":"A Serial shRNA Screen for Roadblocks to Reprogramming Identifies the Protein Modifier SUMO2.","date":"2016","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26947976","citation_count":49,"is_preprint":false},{"pmid":"29891701","id":"PMC_29891701","title":"SUMO2 and SUMO3 redundantly prevent a noncanonical type I interferon response.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29891701","citation_count":48,"is_preprint":false},{"pmid":"29352108","id":"PMC_29352108","title":"DeSUMOylation of MKK7 kinase by the SUMO2/3 protease SENP3 potentiates lipopolysaccharide-induced inflammatory signaling in macrophages.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29352108","citation_count":44,"is_preprint":false},{"pmid":"9833880","id":"PMC_9833880","title":"Insertion of a bovine SMT3B gene in NS4B and duplication of NS3 in a bovine viral diarrhea virus genome correlate with the cytopathogenicity of the virus.","date":"1998","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/9833880","citation_count":43,"is_preprint":false},{"pmid":"21830832","id":"PMC_21830832","title":"Absolute SILAC-compatible expression strain allows Sumo-2 copy number determination in clinical samples.","date":"2011","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/21830832","citation_count":41,"is_preprint":false},{"pmid":"25406032","id":"PMC_25406032","title":"Modification of DBC1 by SUMO2/3 is crucial for p53-mediated apoptosis in response to DNA damage.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25406032","citation_count":39,"is_preprint":false},{"pmid":"9891849","id":"PMC_9891849","title":"Characterization of mouse ubiquitin-like SMT3A and SMT3B cDNAs and gene/pseudogenes.","date":"1998","source":"Biochemistry and molecular biology international","url":"https://pubmed.ncbi.nlm.nih.gov/9891849","citation_count":37,"is_preprint":false},{"pmid":"25352045","id":"PMC_25352045","title":"SUMO2/3 is associated with ubiquitinated protein aggregates in the mouse neocortex after middle cerebral artery occlusion.","date":"2014","source":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/25352045","citation_count":37,"is_preprint":false},{"pmid":"11283016","id":"PMC_11283016","title":"A novel human striated muscle RING zinc finger protein, SMRZ, interacts with SMT3b via its RING domain.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11283016","citation_count":36,"is_preprint":false},{"pmid":"22891650","id":"PMC_22891650","title":"Moderate hypothermia induces marked increase in levels and nuclear accumulation of SUMO2/3-conjugated proteins in neurons.","date":"2012","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22891650","citation_count":36,"is_preprint":false},{"pmid":"32049023","id":"PMC_32049023","title":"SENP3 Suppresses Osteoclastogenesis by De-conjugating SUMO2/3 from IRF8 in Bone Marrow-Derived Monocytes.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32049023","citation_count":35,"is_preprint":false},{"pmid":"38201212","id":"PMC_38201212","title":"Paralogue-Specific Roles of SUMO1 and SUMO2/3 in Protein Quality Control and Associated Diseases.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/38201212","citation_count":34,"is_preprint":false},{"pmid":"25497329","id":"PMC_25497329","title":"Proteome-wide analysis of SUMO2 targets in response to pathological DNA replication stress in human cells.","date":"2014","source":"DNA repair","url":"https://pubmed.ncbi.nlm.nih.gov/25497329","citation_count":32,"is_preprint":false},{"pmid":"25857621","id":"PMC_25857621","title":"Involvement of activated SUMO-2 conjugation in cardiomyopathy.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25857621","citation_count":32,"is_preprint":false},{"pmid":"26511642","id":"PMC_26511642","title":"SENP3 regulates the global protein turnover and the Sp1 level via antagonizing SUMO2/3-targeted ubiquitination and degradation.","date":"2015","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/26511642","citation_count":30,"is_preprint":false},{"pmid":"27343429","id":"PMC_27343429","title":"The SUMO2/3 specific E3 ligase ZNF451-1 regulates PML stability.","date":"2016","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27343429","citation_count":30,"is_preprint":false},{"pmid":"30201799","id":"PMC_30201799","title":"Acetylation of SUMO2 at lysine 11 favors the formation of non-canonical SUMO chains.","date":"2018","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/30201799","citation_count":29,"is_preprint":false},{"pmid":"21291420","id":"PMC_21291420","title":"SUMO2 and SUMO3 transcription is differentially regulated by oxidative stress in an Sp1-dependent manner.","date":"2011","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/21291420","citation_count":28,"is_preprint":false},{"pmid":"26627832","id":"PMC_26627832","title":"Non-native Conformers of Cystic Fibrosis Transmembrane Conductance Regulator NBD1 Are Recognized by Hsp27 and Conjugated to SUMO-2 for Degradation.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26627832","citation_count":26,"is_preprint":false},{"pmid":"34032148","id":"PMC_34032148","title":"LncRNA SNHG3 Promotes Proliferation and Metastasis of Non-Small-Cell Lung Cancer Cells Through miR-515-5p/SUMO2 Axis.","date":"2021","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/34032148","citation_count":25,"is_preprint":false},{"pmid":"24971350","id":"PMC_24971350","title":"High glucose induces sumoylation of Smad4 via SUMO2/3 in mesangial cells.","date":"2014","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/24971350","citation_count":25,"is_preprint":false},{"pmid":"23358114","id":"PMC_23358114","title":"PIASγ enhanced SUMO-2 modification of Nurr1 activation-function-1 domain limits Nurr1 transcriptional synergy.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23358114","citation_count":24,"is_preprint":false},{"pmid":"24971888","id":"PMC_24971888","title":"Comprehensive identification of SUMO2/3 targets and their dynamics during mitosis.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24971888","citation_count":22,"is_preprint":false},{"pmid":"21632113","id":"PMC_21632113","title":"The mouse small ubiquitin-like modifier-2 (SUMO-2) inhibits interleukin-12 (IL-12) production in mature dendritic cells by blocking the translocation of the p65 subunit of NFκB into the nucleus.","date":"2011","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21632113","citation_count":22,"is_preprint":false},{"pmid":"39982984","id":"PMC_39982984","title":"SUMO2/3 conjugation of TDP-43 protects against aggregation.","date":"2025","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/39982984","citation_count":21,"is_preprint":false},{"pmid":"30559154","id":"PMC_30559154","title":"SUMOylation by SUMO2 is implicated in the degradation of misfolded ataxin-7 via RNF4 in SCA7 models.","date":"2019","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/30559154","citation_count":21,"is_preprint":false},{"pmid":"25607652","id":"PMC_25607652","title":"KSHV latent protein LANA2 inhibits sumo2 modification of p53.","date":"2015","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/25607652","citation_count":20,"is_preprint":false},{"pmid":"35864967","id":"PMC_35864967","title":"SUMOylation of Nuclear γ-Actin by SUMO2 supports DNA Damage Repair against Myocardial Ischemia-Reperfusion Injury.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35864967","citation_count":19,"is_preprint":false},{"pmid":"23673635","id":"PMC_23673635","title":"SUMO2/3 modification of cyclin E contributes to the control of replication origin firing.","date":"2013","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/23673635","citation_count":19,"is_preprint":false},{"pmid":"19919826","id":"PMC_19919826","title":"The p150 subunit of CAF-1 causes association of SUMO2/3 with the DNA replication foci.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19919826","citation_count":19,"is_preprint":false},{"pmid":"22178731","id":"PMC_22178731","title":"Ubiquitin-intein and SUMO2-intein fusion systems for enhanced protein production and purification.","date":"2011","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/22178731","citation_count":18,"is_preprint":false},{"pmid":"38327870","id":"PMC_38327870","title":"SumoPred-PLM: human SUMOylation and SUMO2/3 sites Prediction using Pre-trained Protein Language Model.","date":"2024","source":"NAR genomics and bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/38327870","citation_count":17,"is_preprint":false},{"pmid":"32910521","id":"PMC_32910521","title":"Small ubiquitin-like modifier 2 (SUMO2) is critical for memory processes in mice.","date":"2020","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/32910521","citation_count":17,"is_preprint":false},{"pmid":"29700214","id":"PMC_29700214","title":"Silencing SUMO2 promotes protection against degradation and apoptosis of nucleus pulposus cells through p53 signaling pathway in intervertebral disc degeneration.","date":"2018","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/29700214","citation_count":17,"is_preprint":false},{"pmid":"22945749","id":"PMC_22945749","title":"Transient ischemia induces massive nuclear accumulation of SUMO2/3-conjugated proteins in spinal cord neurons.","date":"2012","source":"Spinal cord","url":"https://pubmed.ncbi.nlm.nih.gov/22945749","citation_count":17,"is_preprint":false},{"pmid":"27016777","id":"PMC_27016777","title":"Dynamic regulation of HIF1Α stability by SUMO2/3 and SENP3 in the human placenta.","date":"2016","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/27016777","citation_count":16,"is_preprint":false},{"pmid":"27071615","id":"PMC_27071615","title":"IL-6 induced proliferation and cytotoxic activity of CD8(+) T cells is elevated by SUMO2 overexpression.","date":"2016","source":"Archives of pharmacal research","url":"https://pubmed.ncbi.nlm.nih.gov/27071615","citation_count":16,"is_preprint":false},{"pmid":"24424631","id":"PMC_24424631","title":"Structural insights into the SENP6 Loop1 structure in complex with SUMO2.","date":"2014","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/24424631","citation_count":16,"is_preprint":false},{"pmid":"18639523","id":"PMC_18639523","title":"SMT3IP1, a nucleolar SUMO-specific protease, deconjugates SUMO-2 from nucleolar and cytoplasmic nucleophosmin.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18639523","citation_count":15,"is_preprint":false},{"pmid":"35487252","id":"PMC_35487252","title":"SUMO2-mediated SUMOylation of SH3GLB1 promotes ionizing radiation-induced hypertrophic cardiomyopathy through mitophagy activation.","date":"2022","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35487252","citation_count":14,"is_preprint":false},{"pmid":"27767176","id":"PMC_27767176","title":"Sumoylation-independent activation of Calcineurin-NFAT-signaling via SUMO2 mediates cardiomyocyte hypertrophy.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27767176","citation_count":14,"is_preprint":false},{"pmid":"31584834","id":"PMC_31584834","title":"SUMO2 regulates vascular endothelial function and oxidative stress in mice.","date":"2019","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31584834","citation_count":13,"is_preprint":false},{"pmid":"32892251","id":"PMC_32892251","title":"Guanosine modulates SUMO2/3-ylation in neurons and astrocytes via adenosine receptors.","date":"2020","source":"Purinergic signalling","url":"https://pubmed.ncbi.nlm.nih.gov/32892251","citation_count":13,"is_preprint":false},{"pmid":"35235714","id":"PMC_35235714","title":"Multiplexed Delivery of Synthetic (Un)Conjugatable Ubiquitin and SUMO2 Enables Simultaneous Monitoring of Their Localization and Function in Live Cells.","date":"2022","source":"Chembiochem : a European journal of chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/35235714","citation_count":13,"is_preprint":false},{"pmid":"41057295","id":"PMC_41057295","title":"Ferroptosis-induced SUMO2 lactylation counteracts ferroptosis by enhancing ACSL4 degradation in lung adenocarcinoma.","date":"2025","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41057295","citation_count":12,"is_preprint":false},{"pmid":"31625212","id":"PMC_31625212","title":"The requirement of SUMO2/3 for SENP2 mediated extraembryonic and embryonic development.","date":"2019","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/31625212","citation_count":12,"is_preprint":false},{"pmid":"25762490","id":"PMC_25762490","title":"SUMO2 overexpression enhances the generation and function of interleukin-17-producing CD8⁺ T cells in mice.","date":"2015","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/25762490","citation_count":12,"is_preprint":false},{"pmid":"37942585","id":"PMC_37942585","title":"NDP52 SUMOylation contributes to low-dose X-rays-induced cardiac hypertrophy through PINK1/Parkin-mediated mitophagy via MUL1/SUMO2 signalling.","date":"2023","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37942585","citation_count":12,"is_preprint":false},{"pmid":"29326161","id":"PMC_29326161","title":"SUMO2/3 modification of activating transcription factor 5 (ATF5) controls its dynamic translocation at the centrosome.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29326161","citation_count":12,"is_preprint":false},{"pmid":"18081309","id":"PMC_18081309","title":"Basic folded and low-populated locally disordered conformers of SUMO-2 characterized by NMR spectroscopy at varying pressures.","date":"2007","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18081309","citation_count":12,"is_preprint":false},{"pmid":"36334780","id":"PMC_36334780","title":"Structural Basis for the SUMO2 Isoform Specificity of SENP7.","date":"2022","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/36334780","citation_count":11,"is_preprint":false},{"pmid":"34257372","id":"PMC_34257372","title":"Differential effects of SUMO1 and SUMO2 on circadian protein PER2 stability and function.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34257372","citation_count":11,"is_preprint":false},{"pmid":"31830143","id":"PMC_31830143","title":"Identification of viral SIM-SUMO2-interaction inhibitors for treating primary effusion lymphoma.","date":"2019","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/31830143","citation_count":11,"is_preprint":false},{"pmid":"25748227","id":"PMC_25748227","title":"Regulation of SUMO2 target proteins by the proteasome in human cells exposed to replication stress.","date":"2015","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/25748227","citation_count":11,"is_preprint":false},{"pmid":"37009224","id":"PMC_37009224","title":"Characterizing the differential distribution and targets of Sumo1 and Sumo2 in the mouse brain.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37009224","citation_count":10,"is_preprint":false},{"pmid":"22922005","id":"PMC_22922005","title":"Post-translational modification of the RhoGTPase activating protein 21, ARHGAP21, by SUMO2/3.","date":"2012","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/22922005","citation_count":10,"is_preprint":false},{"pmid":"33989451","id":"PMC_33989451","title":"Downregulation of SUMO2 inhibits hepatocellular carcinoma cell proliferation, migration and invasion.","date":"2021","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/33989451","citation_count":9,"is_preprint":false},{"pmid":"33539797","id":"PMC_33539797","title":"Selective-cerebral-hypothermia-induced neuroprotection against-focal cerebral ischemia/reperfusion injury is associated with an increase in SUMO2/3 conjugation.","date":"2021","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/33539797","citation_count":9,"is_preprint":false},{"pmid":"34174262","id":"PMC_34174262","title":"Prasugrel anti-ischemic effect in rats: Modulation of hippocampal SUMO2/3-IкBα/Ubc9 and SIRT-1/miR-22 trajectories.","date":"2021","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34174262","citation_count":9,"is_preprint":false},{"pmid":"36346822","id":"PMC_36346822","title":"A structural dynamics model for how CPEB3 binding to SUMO2 can regulate translational control in dendritic spines.","date":"2022","source":"PLoS computational biology","url":"https://pubmed.ncbi.nlm.nih.gov/36346822","citation_count":9,"is_preprint":false},{"pmid":"25245533","id":"PMC_25245533","title":"Interleukin-32α downregulates the activity of the B-cell CLL/lymphoma 6 protein by inhibiting protein kinase Cε-dependent SUMO-2 modification.","date":"2014","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25245533","citation_count":9,"is_preprint":false},{"pmid":"38513457","id":"PMC_38513457","title":"FEN1 upregulation mediated by SUMO2 via antagonizing proteasomal degradation promotes hepatocellular carcinoma stemness.","date":"2024","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38513457","citation_count":8,"is_preprint":false},{"pmid":"33732350","id":"PMC_33732350","title":"Inhibition of SUMO2/3 antagonizes isoflurane-induced cancer-promoting effect in hepatocellular carcinoma Hep3B cells.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/33732350","citation_count":8,"is_preprint":false},{"pmid":"37473957","id":"PMC_37473957","title":"Overexpression of SENP3 promotes PPAR-γ transcription through the increase of HIF-1α stability via SUMO2/3 and participates in molecular mechanisms of osteoporosis.","date":"2023","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/37473957","citation_count":8,"is_preprint":false},{"pmid":"37338025","id":"PMC_37338025","title":"SUMO2/3 promotes the progression and oxaliplatin resistance of colorectal cancer through facilitating the SUMOylation at Ku80-K307.","date":"2023","source":"BioFactors (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/37338025","citation_count":7,"is_preprint":false},{"pmid":"29512695","id":"PMC_29512695","title":"SUMO2 modification of Aurora B and its impact on follicular development and atresia in the mouse ovary.","date":"2018","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29512695","citation_count":7,"is_preprint":false},{"pmid":"31045562","id":"PMC_31045562","title":"Noncovalent structure of SENP1 in complex with SUMO2.","date":"2019","source":"Acta crystallographica. Section F, Structural biology communications","url":"https://pubmed.ncbi.nlm.nih.gov/31045562","citation_count":7,"is_preprint":false},{"pmid":"36656084","id":"PMC_36656084","title":"The allosteric effect of the upper half of SENP1 contributes to its substrate selectivity for SUMO1 over SUMO2.","date":"2023","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/36656084","citation_count":7,"is_preprint":false},{"pmid":"39000276","id":"PMC_39000276","title":"SARS-CoV-2 Nucleocapsid Protein Induces Tau Pathological Changes That Can Be Counteracted by SUMO2.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39000276","citation_count":7,"is_preprint":false},{"pmid":"40047257","id":"PMC_40047257","title":"Genetic and pharmacologic enhancement of SUMO2 conjugation prevents and reverses cognitive impairment and synaptotoxicity in a preclinical model of Alzheimer's disease.","date":"2025","source":"Alzheimer's & dementia : the journal of the Alzheimer's Association","url":"https://pubmed.ncbi.nlm.nih.gov/40047257","citation_count":6,"is_preprint":false},{"pmid":"18243776","id":"PMC_18243776","title":"Schistosoma mansoni encodes SMT3B and SMT3C molecules responsible for post-translational modification of cellular proteins.","date":"2007","source":"Parasitology international","url":"https://pubmed.ncbi.nlm.nih.gov/18243776","citation_count":6,"is_preprint":false},{"pmid":"37403456","id":"PMC_37403456","title":"SENP5 deteriorates traumatic brain injury via SUMO2-dependent suppression of E2F1 SUMOylation.","date":"2023","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/37403456","citation_count":6,"is_preprint":false},{"pmid":"37890757","id":"PMC_37890757","title":"Aberrant SUMO2/3 modification of RUNX1 upon SENP1 inhibition is linked to the development of diabetic retinopathy in mice.","date":"2023","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/37890757","citation_count":6,"is_preprint":false},{"pmid":"24971752","id":"PMC_24971752","title":"SUMO-2 promotes mRNA translation by enhancing interaction between eIF4E and eIF4G.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24971752","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50582,"output_tokens":10128,"usd":0.151833,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20363,"output_tokens":8285,"usd":0.15447,"stage2_stop_reason":"end_turn"},"total_usd":0.306303,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"SUMO-2 and SUMO-3 contain an internal consensus SUMOylation motif (ψKXE), enabling SAE1/SAE2 (E1) and Ubc9 (E2) to catalyze the formation of polymeric SUMO-2 and SUMO-3 chains on protein substrates in vitro; SUMO-2 chains were also detected in vivo. This chain-forming capacity is not shared by SUMO-1.\",\n      \"method\": \"In vitro conjugation assay with purified SAE1/SAE2 and Ubc9; in vivo detection of SUMO-2 chains\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified enzymes combined with in vivo confirmation, replicated across subsequent literature\",\n      \"pmids\": [\"11451954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A SUMO-interacting motif (SIM) was defined that forms a beta-strand binding to the beta2-strand of SUMO2 in parallel or antiparallel orientation; a stretch of acidic/phosphorylated residues flanking the SIM determines specificity for distinct SUMO paralogues including SUMO2 versus SUMO1.\",\n      \"method\": \"Yeast two-hybrid, bioinformatics, NMR spectroscopy mapping of binding surfaces\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional binding surface mapping, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"16524884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Crystal structure of truncated human SUMO-2 (residues 9–93) determined at 1.2 Å resolution; the fold (βββαββαβ) is identical to ubiquitin and SUMO-1, but a surface region near the C-terminus shows significantly different charge distribution compared to SUMO-1, which may explain distinct intracellular localizations.\",\n      \"method\": \"X-ray crystallography (molecular replacement, R3 space group, 1.2 Å resolution)\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with direct structural comparison to SUMO-1\",\n      \"pmids\": [\"15479240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PIASy, a PIAS-family SUMO E3 ligase, binds mitotic chromosomes, recruits Ubc9, and is specifically required for SUMO-2 conjugation of Topoisomerase-II on mitotic chromosomes in Xenopus egg extracts; PIASy depletion eliminated essentially all chromosomal SUMO-2-conjugated species and blocked anaphase sister chromatid segregation.\",\n      \"method\": \"Immunodepletion from Xenopus egg extracts, chromatin binding assays, epistasis with PIASy chromatin-binding mutants\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reconstituted Xenopus system with depletion/rescue and mutant analysis, defines E3 ligase-substrate relationship\",\n      \"pmids\": [\"15933717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SUSP1 (SENP/Ulp family protease) localizes in the nucleoplasm and has strong paralogue bias toward SUMO2/3; it acts preferentially on substrates bearing three or more SUMO2/3 moieties, antagonizing formation of highly conjugated SUMO2/3 species. Depletion of SUSP1 causes redistribution of EGFP-SUMO2/3 into enlarged PML bodies.\",\n      \"method\": \"Vinyl sulfone inhibitors, model substrate assays, siRNA depletion with fluorescence microscopy of EGFP-SUMO fusions\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical activity assay with specific inhibitors plus cellular imaging, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"17000875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Borealin (chromosomal passenger complex component) is preferentially modified by SUMO2/3 during early mitosis. The SUMO E3 ligase RanBP2 interacts with the CPC and stimulates SUMO2/3 modification of Borealin in vitro and in vivo; the SUMO isopeptidase SENP3 specifically binds Borealin and removes SUMO2/3, delineating a mitotic SUMO2/3 conjugation–deconjugation cycle.\",\n      \"method\": \"Co-immunoprecipitation, in vitro SUMOylation assay, siRNA knockdown, cell synchronization\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution plus reciprocal co-IP and in vivo validation, single lab multiple orthogonal methods\",\n      \"pmids\": [\"18946085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BMAL1 is predominantly conjugated to poly-SUMO2/3 (not SUMO1) under physiological circadian conditions; this modification localizes BMAL1 to PML nuclear bodies and promotes both its transactivation and ubiquitin-dependent proteasomal degradation. Mutation of the BMAL1 sumoylation site (K259) blocked ubiquitination and proteolysis; covalent SUMO3 attachment restored these effects. SUSP1 (SUMO2/3-specific protease) abolished both sumoylation and ubiquitination of BMAL1.\",\n      \"method\": \"Site-directed mutagenesis, co-immunoprecipitation, immunofluorescence, proteasome inhibitor treatment, SUSP1 overexpression/knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, mutagenesis, pharmacological and genetic manipulation, multiple orthogonal readouts in single study\",\n      \"pmids\": [\"18644859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mass spectrometry identified 103 SUMO-2 acceptor lysines in endogenous target proteins: 76 in canonical ψKxE motifs, 8 in an inverted consensus [ED]xK[VILFP], and 16 in a newly defined hydrophobic cluster SUMOylation motif (HCSM). Cross-talk between SUMOylation and phosphorylation was observed with a preferred spacer of four residues.\",\n      \"method\": \"Site-specific mass spectrometry proteomics using mutant SUMO-2 with engineered trypsin cleavage site\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct MS identification of modification sites in endogenous proteins at proteome scale, validated on individual substrates\",\n      \"pmids\": [\"20797634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SENP3, a SUMO2/3-specific protease, is stabilized by low-dose H2O2 (mild oxidative stress), co-localizes with PML bodies, and removes SUMO2/3 from PML; this de-conjugation is responsible for accelerated cell proliferation. Only SUMOylated PML (not a SUMOylation-deficient mutant) inhibits cell proliferation, demonstrating that SUMO2/3 conjugation of PML suppresses proliferation.\",\n      \"method\": \"siRNA knockdown of SENP3, reconstitution with wild-type vs. SUMOylation-mutant PML, cell proliferation assays, co-localization imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via reconstitution with SUMOylation-deficient mutant, multiple orthogonal approaches, clearly defines mechanism\",\n      \"pmids\": [\"20181954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PIAS1 is an E3 SUMO ligase for both SUMO-1 and SUMO-2 modification of mutant huntingtin (HTT). SUMO-2 modification of HTT regulates accumulation of insoluble HTT in HeLa cells in a manner mimicking proteasome inhibition; this can be modulated by PIAS1 overexpression and acute knockdown.\",\n      \"method\": \"Systematic E3 ligase screen, in vitro SUMOylation assays, co-immunoprecipitation, insoluble fraction analysis, PIAS1 knockdown/overexpression\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic screen with follow-up biochemical assays in single lab; E3 identification validated in vitro and in cell\",\n      \"pmids\": [\"23871671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cyclin E is dynamically SUMOylated by SUMO2/3 on chromatin during early S phase in a Xenopus cell-free system, independently of Cdk2 activity and origin activation. Cyclin E is the predominant SUMO2/3 target on chromatin in early S phase; SUMO pathway inhibition increased the density of activated replication origins, indicating SUMO2/3-cyclin E conjugation limits replication origin firing.\",\n      \"method\": \"Xenopus cell-free replication system, immunodepletion, chromatin fractionation, SUMO pathway inhibition\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cell-free reconstitution system with depletion/add-back, direct functional readout (origin firing density), single lab multiple methods\",\n      \"pmids\": [\"23673635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Proteome-wide identification using SUMO2(T90K) with engineered Lys-C cleavage site revealed >1000 sumoylated lysines in 539 proteins, enabling systematic study of SUMO2 modification sites involved in cell cycle, transcription, and DNA repair.\",\n      \"method\": \"His6-SUMO2(T90K) expression, Lys-C digestion, diGly remnant immunoprecipitation, mass spectrometry\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — novel engineered method enabling proteome-scale direct identification of SUMO2 acceptor sites, validated by multiple independent analyses\",\n      \"pmids\": [\"24782567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DBC1 (SIRT1 inhibitor) is specifically modified by SUMO2/3, not SUMO1, in response to DNA damage. ATM/ATR-mediated phosphorylation of DBC1 switches its binding from SENP1 to PIAS3, increasing SUMO2/3 conjugation. SUMOylated DBC1 enhances DBC1-SIRT1 interaction, releasing p53 from SIRT1-mediated repression to enable p53-dependent apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of PIAS3/SENP1/SUMO2/3, SUMOylation-deficient DBC1 mutant, etoposide treatment, apoptosis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis via multiple knockdowns and SUMOylation-deficient mutant, identifies upstream kinase signal and downstream effector, multiple orthogonal methods\",\n      \"pmids\": [\"25406032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SUMO2 is the predominantly expressed SUMO isoform during embryogenesis; Sumo2-null mouse embryos exhibit severe developmental delay and die at ~E10.5, whereas Sumo3-null mice are viable, demonstrating that SUMO2 is essential while SUMO3 is dispensable for embryonic development.\",\n      \"method\": \"Gene knockout mouse models (Sumo2-/- and Sumo3-/- null mutants), genetic analysis of compound mutants\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function mouse genetics with clear developmental phenotype, compound mutant analysis across multiple litters\",\n      \"pmids\": [\"24891386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SUMO-2 orchestrates chromatin modifiers in the mammalian DNA damage response (DDR): 20 SUMO-2 conjugates were upregulated and 33 downregulated upon MMS treatment. SUMOylated JARID1B (KDM5B) is ubiquitylated by RNF4 (SUMO-targeted ubiquitin ligase) and degraded by the proteasome; in contrast, JARID1C is recruited to chromatin to demethylate H3K4, demonstrating substrate-specific functional outcomes of SUMO-2 modification in the DDR.\",\n      \"method\": \"Quantitative SUMO-2 proteomics (SILAC), siRNA knockdown, chromatin fractionation, ubiquitylation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative proteomics combined with functional mechanistic follow-up on specific substrates, single lab multiple orthogonal methods\",\n      \"pmids\": [\"25772364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Non-native conformers of CFTR NBD1 are recognized by Hsp27, which collaborates with Ubc9 to selectively conjugate SUMO-2 (not other SUMO paralogs) to NBD1 at K447; this SUMO-2 modification leads to RNF4-dependent ubiquitylation and proteasomal degradation. SUMOylation was greater for F508del NBD1 than wild-type in vitro with purified components, and was reduced by stabilizing mutations.\",\n      \"method\": \"In vitro SUMOylation with purified components, site-directed mutagenesis (K447R), Hsp27 co-immunoprecipitation, intrinsic fluorescence, proteasome assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified components, mutagenesis, conformational studies; single lab multiple orthogonal methods\",\n      \"pmids\": [\"26627832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZNF451 isoform 1 (ZNF451-1) functions as a SUMO2/3-specific E3 ligase for PML and selected PML body components in vitro; in vivo, ZNF451-1 RNAi depletion stabilizes PML and increases PML body number, indicating it fine-tunes physiological PML levels cooperatively with RNF4.\",\n      \"method\": \"In vitro SUMOylation assays, mutational analysis of E3 ligase mechanism, RNAi depletion, PML body quantification by immunofluorescence\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro E3 assay plus cellular RNAi phenotype, single lab, confirms SUMO2/3 specificity\",\n      \"pmids\": [\"27343429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SUMO2/3 conjugation of PCNA (specifically SUMO2, not SUMO1 or SUMO3) is induced on transcribed chromatin by the RNAPII-bound helicase RECQ5; SUMO2-PCNA enriches histone chaperones CAF1 and FACT via their SUMO-interacting motifs, enhances CAF1-dependent histone deposition, increases repressive chromatin marks at common fragile sites, and dislodges RNAPII to resolve transcription-replication conflicts.\",\n      \"method\": \"Proteomic analysis of SUMO2-PCNA complexes, SIM-dependent interaction assays, histone deposition assays, ChIP, DSB quantification in RECQ5-deficient cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic identification of SUMO2-PCNA interactors plus functional chromatin and DNA break assays, paralog-specific (SUMO2 vs. SUMO1/3) distinction established\",\n      \"pmids\": [\"30006506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Acetylation of SUMO2 at lysine K11 is reversible, with SIRT1 acting as the K11 deacetylase. In a purified in vitro system, K11 acetylation impairs SUMO2/3 chain formation and restricts chain length. Mimicking K11 acetylation in cells alters chain architecture by favoring K5- and K35-linked chains while inhibiting K7 and K21 linkages, demonstrating K11 acetylation as a modulator of SUMO2/3 chain topology.\",\n      \"method\": \"In vitro chain formation assay with acetyl-mimic SUMO2, MS-based SUMO proteomics, SIRT1 deacetylase identification, acetyl-mimic K11Q mutant analysis in cells\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution plus proteomics-based identification of chain linkages, SIRT1 identified as eraser, single lab multiple methods\",\n      \"pmids\": [\"30201799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of SUMO2/3 (but not SUMO1) results in a spontaneous, potent type I interferon response that is independent of all known IFN-inducing pathways (IRF3 and IRF7 not required), demonstrating that SUMO2 and SUMO3 redundantly and specifically suppress a noncanonical IFN induction mechanism.\",\n      \"method\": \"Genetic knockout of SUMO2 and SUMO3, IRF3/IRF7 double-knockout epistasis, IFN response measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis across multiple knockout combinations, defines SUMO2/3 pathway specificity versus SUMO1\",\n      \"pmids\": [\"29891701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DeSUMOylation of MKK7 by the SUMO2/3-specific protease SENP3 promotes MKK7 binding to JNK, enhancing JNK phosphorylation and downstream TLR4 inflammatory signaling in macrophages. ROS-dependent SENP3 accumulation and MKK7 deSUMOylation occur rapidly after LPS stimulation. SENP3 conditional knockout in myeloid cells compromises TLR4 signaling and protects against septic shock.\",\n      \"method\": \"Conditional SENP3 knockout mice, LPS stimulation assays, JNK phosphorylation measurement, co-immunoprecipitation of MKK7-JNK, in vivo septic shock model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with clean phenotype, co-IP defining substrate-enzyme interaction, mechanistic pathway placement via JNK phosphorylation readout\",\n      \"pmids\": [\"29352108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SENP6, a poly-SUMO2/3-specific protease, regulates the constitutive centromere-associated network (CCAN) through group de-SUMOylation of >180 interconnected proteins. SENP6 deficiency impairs CENP-T, CENP-W, and CENP-A accumulation at centromeres, causes G2/M accumulation and micronuclei formation. Increased SUMO chains do not lead to proteasomal degradation of CCAN subunits, demonstrating a proteolysis-independent function of SUMO2/3 polymers.\",\n      \"method\": \"SENP6 knockdown proteomics, cell cycle analysis, immunofluorescence of centromere proteins, proteasome inhibitor experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative proteomics plus functional centromere/cell cycle readouts, proteolysis-independent mechanism established by proteasome inhibition controls\",\n      \"pmids\": [\"31485003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SENP3-mediated deSUMOylation of IRF8 at K310 (SUMO3 modification) in bone-marrow-derived monocytes promotes osteoclast differentiation by upregulating NFATc1; SENP3 deficiency in BMDMs increases IRF8 SUMO3 modification and suppresses osteoclastogenesis, protecting against ovariectomy-induced bone loss.\",\n      \"method\": \"Conditional SENP3 knockout mice (myeloid-specific), co-immunoprecipitation, site-specific mutagenesis (K310), ovariectomy bone loss model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mice with defined in vivo bone phenotype, site-specific mutation identifying modification site, mechanistic pathway placement via NFATc1\",\n      \"pmids\": [\"32049023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional deletion of SUMO2 predominantly in forebrain neurons causes marked impairments in episodic and fear memory and a significant deficit in hippocampal long-term potentiation maintenance, without constitutive changes in gene expression or neuronal morphology, implicating dynamic SUMO2 conjugation in synaptic plasticity.\",\n      \"method\": \"Conditional Sumo2 knockout mice (forebrain neuron-specific), behavioral cognitive tests, electrophysiology (LTP measurement)\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional neuron-specific KO with LTP electrophysiology and behavioral phenotypes, multiple readouts, excludes morphological/transcriptional explanations\",\n      \"pmids\": [\"32910521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"During oxidative stress, TDP-43 is SUMOylated by SUMO2/3 via the E3 ligase PIAS4 and enriches in cytoplasmic stress granules (SGs); pharmacological inhibition of SUMO2/3-ylation or PIAS4 depletion causes irreversible TDP-43 aggregation. RNA binding to TDP-43 antagonizes PIAS4-mediated SUMO2/3-ylation, while RNA dissociation promotes it, indicating SUMO2/3 conjugation stabilizes cytosolic RNA-free TDP-43 against aggregation.\",\n      \"method\": \"PIAS4 depletion, pharmacological inhibition, stress granule assembly/disassembly experiments, co-IP, RNA-binding mutant analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — identifies E3 ligase, establishes RNA-dependence of modification, functional rescue with multiple complementary genetic and pharmacological approaches\",\n      \"pmids\": [\"39982984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SUMO2 activates Calcineurin-NFAT signaling and cardiomyocyte hypertrophy through a direct interaction between SUMO2 and calcineurin A (CnA) that promotes CnA nuclear localization; this effect is sumoylation-independent, as a sumoylation-deficient SUMO2-ΔGG mutant replicates the Cn-NFAT activation and hypertrophic phenotype both in vitro and in vivo.\",\n      \"method\": \"cDNA library screen, NFAT luciferase reporter assay, sumoylation-deficient mutant (ΔGG), AAV9-mediated in vivo cardiac SUMO2 expression, co-immunoprecipitation of SUMO2-CnA\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV delivery plus in vitro mechanistic assays with sumoylation-deficient mutant, single lab, direct protein interaction identified\",\n      \"pmids\": [\"27767176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SUMO2 modification of PCNA (via p150 subunit of CAF-1 interaction): the p150 subunit of chromatin assembly factor 1 (CAF-1) interacts directly and preferentially with SUMO2/3 through residues 98-105; p150 depletion causes delocalization of SUMO2/3 from DNA replication foci, and p150 mutants deficient in SUMO2/3 interaction markedly reduce SUMO2/3 at replication foci.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of p150 (residues 98-105), siRNA knockdown, immunofluorescence at BrdU/PCNA replication foci\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mutagenesis confirming binding region plus functional localization readout; published 2009, single lab\",\n      \"pmids\": [\"19919826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structure of the SENP7 catalytic domain bound to SUMO2 reveals that a unique Loop1 insertion in SENP7 makes specific contacts with SUMO2 that are absent in other SENP family members, establishing the structural basis for SENP6/7's SUMO2/3 isoform preference and poly-SUMO2 chain dismantling activity.\",\n      \"method\": \"X-ray crystallography of SENP7-SUMO2 complex, structure-function comparison with SENP2-Loop1 chimera\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation using Loop1 chimera, defines isoform specificity determinants\",\n      \"pmids\": [\"36334780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of SENP2-Loop1 chimera (containing the SENP6/7 Loop1 insertion) in complex with SUMO2 at 2.15 Å shows unique interface contacts exclusive to SENP6/7; the Loop1 chimera displays enhanced proteolytic activity toward diSUMO2 and polySUMO2 substrates, confirming Loop1 as determinant for SUMO2/3 activity and specificity.\",\n      \"method\": \"X-ray crystallography of chimeric SENP2-Loop1/SUMO2 complex, in vitro protease activity assays with diSUMO2 and polySUMO2 substrates\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with functional enzymatic assays, single lab, directly links structural feature to substrate specificity\",\n      \"pmids\": [\"24424631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of SENP1 catalytic domain in noncovalent complex with SUMO2 at 2.62 Å resolution shows that complex formation is driven by polar interactions and limited hydrophobic contacts; the SUMO2 C-terminal QQTGG motif protrudes into the SENP1 catalytic triad, providing the structural basis for SUMO2 maturation and deSUMOylation.\",\n      \"method\": \"X-ray crystallography of SENP1-SUMO2 noncovalent complex\",\n      \"journal\": \"Acta crystallographica. Section F, Structural biology communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure without extensive functional mutagenesis validation, single paper\",\n      \"pmids\": [\"31045562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SMT3IP1 (nucleolar SUMO-specific protease) preferentially removes SUMO-2 from nucleophosmin (NPM) in both nucleolar and cytoplasmic compartments; catalytically inactive SMT3IP1 mutant increases SUMO-2-modified NPM in a dominant-negative manner; SUMO-2 conjugation of cytoplasmic mutant NPM is markedly elevated in an ARF-dependent manner.\",\n      \"method\": \"Yeast two-hybrid identification of NPM as SMT3IP1 substrate, dominant-negative catalytic mutant, ARF-dependent SUMOylation analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid substrate identification with dominant-negative protease mutant validation, single lab\",\n      \"pmids\": [\"18639523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ATF5 is modified by SUMO2/3 at a conserved consensus site; SUMOylation of ATF5 is elevated in G1 phase and diminished in G2/M phase. SUMO2/3 modification disrupts ATF5 interaction with centrosomal proteins, dislodging ATF5 from the centrosome at end of M phase. Blockade of ATF5 SUMOylation deregulates the centrosome cycle, impedes ATF5 translocation, and causes genomic instability and G2/M arrest.\",\n      \"method\": \"Cell cycle synchronization, co-immunoprecipitation with centrosomal proteins, SUMOylation-deficient mutant, genomic instability assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-cycle-resolved modification plus functional mutant phenotype, single lab, multiple readouts\",\n      \"pmids\": [\"29326161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SUMOylation of polyQ-ataxin-7 (polyQ-ATXN7) by SUMO2/3 recruits the SUMO-targeted ubiquitin ligase RNF4; overexpression of RNF4 and/or SUMO2 significantly decreases polyQ-ATXN7 levels and increases its polyubiquitination upon proteasome inhibition, demonstrating a SUMO2-dependent degradation pathway for misfolded ataxin-7.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, proximity ligation assay, RNF4/SUMO2 overexpression, SCA7 knockin mouse model analysis\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and overexpression with polyubiquitination assay, validated in mouse model, single lab\",\n      \"pmids\": [\"30559154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ferroptosis induces lactylation of SUMO2 at K11 (SUMO2-K11la); this modification impairs the interaction between SUMO2 and ACSL4, facilitating ACSL4 degradation, disrupting lipid metabolism, and mitigating ferroptosis in lung adenocarcinoma. AARS1 is the lactyltransferase and HDAC1 is the delactylase for SUMO2-K11la.\",\n      \"method\": \"SUMOylation proteomics, co-IP assays, metabolomic profiling, identification of AARS1 as lactyltransferase and HDAC1 as delactylase, cell-penetrating peptide inhibitor, xenograft models\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus co-IP and functional assays identifying writer/eraser, in vivo xenograft validation, single lab\",\n      \"pmids\": [\"41057295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SUMO2 interacts with and promotes cap-dependent mRNA translation by enhancing the interaction between eIF4E and eIF4G to form the active eIF4F complex; SUMO2 overexpression partially reverses the effect of 4EGI-1 (eIF4E/eIF4G interaction inhibitor), while SUMO2 knockdown impairs cap-dependent translation and promotes apoptosis.\",\n      \"method\": \"Co-immunoprecipitation of eIF4E-eIF4G, SUMO2 overexpression/shRNA knockdown, 4EGI-1 rescue assay, polysome profiling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with partial mechanistic follow-up, single lab, not independently replicated\",\n      \"pmids\": [\"24971752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SMRZ (striated muscle RING zinc finger protein) interacts with SMT3b (SUMO2) through its RING domain; this interaction is abolished by mutagenesis of conserved RING domain residues, and SMRZ localizes to the nucleus in muscle cells.\",\n      \"method\": \"Co-immunoprecipitation, RING domain mutagenesis, transient transfection with nuclear localization imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP with mutagenesis, single lab, no functional downstream consequence established for SUMO2 itself\",\n      \"pmids\": [\"11283016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ARHGAP21 (a RhoGAP modulating cell migration via Cdc42 and FAK) is specifically modified by SUMO2/3 at lysine K1443; SUMO2/3-modified ARHGAP21 co-localizes with SUMO2/3 in cytoplasm and membrane compartments, and its SUMOylation may be related to cell proliferation.\",\n      \"method\": \"Mass spectrometry identification of modified form, co-immunoprecipitation, in vitro SUMOylation, immunofluorescence\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vitro SUMOylation plus co-IP, site mapped, but functional consequence only suggested, single lab\",\n      \"pmids\": [\"22922005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"γ-actin is SUMOylated by SUMO2 at K68 and K284 in cardiomyocytes; SUMOylation promotes nuclear deposition of γ-actin and DNA damage repair. SUMO2 silencing decreased nuclear γ-actin and exacerbated DNA damage; K68R/K284R double mutant γ-actin failed to protect cardiomyocytes against hypoxia-reoxygenation challenge.\",\n      \"method\": \"Strep-SUMO2 affinity purification with MALDI-TOF-MS identification, site-directed mutagenesis (K68R/K284R), in vivo myocardial infarction model, H9c2 hypoxia-reoxygenation model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identified by purification/MS, mutagenesis of acceptor lysines, functional readout in multiple models, single lab\",\n      \"pmids\": [\"35864967\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SUMO2 forms polymeric chains (via its internal ψKXE motif) using the SAE1/SAE2 E1 and Ubc9 E2 conjugating machinery; it is conjugated to hundreds of nuclear substrates—especially under stress conditions—by E3 ligases including PIASy, RanBP2, ZNF451-1, and PIAS4, and is removed by SUMO2/3-specific proteases (SENP3, SENP6, SENP7, SUSP1) to regulate protein stability (via the STUbL/RNF4-proteasome axis), DNA replication origin firing, mitotic chromosome segregation, DNA damage responses, circadian timing, type I interferon suppression, synaptic plasticity, and embryonic development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SUMO2 is a small ubiquitin-like modifier that, unlike SUMO1, carries an internal \\u03c8KxE consensus motif allowing it to be polymerized into SUMO2/3 chains by the SAE1/SAE2 E1 and Ubc9 E2 machinery, building a dynamic conjugation system that decorates hundreds of predominantly nuclear substrates [#0, #7, #11]. Substrate-selective conjugation is directed by distinct E3 ligases\\u2014PIASy on mitotic chromosomes, RanBP2 within the chromosomal passenger complex, PIAS3 in the DNA damage response, PIAS4 on stress-granule TDP-43, and ZNF451-1 at PML bodies\\u2014and is read out by SUMO-interacting-motif (SIM) proteins whose acidic/phosphorylated flanks tune paralog selectivity [#1, #3, #5, #12, #16, #24]. A major functional output is coupling to protein turnover: SUMO2 chains recruit the STUbL RNF4 to drive proteasomal degradation of substrates such as JARID1B, CFTR NBD1, and misfolded polyQ proteins [#14, #15, #32]. Through these conjugation\\u2013deconjugation cycles SUMO2 governs mitotic chromosome segregation and centromere assembly, restrains DNA replication origin firing via cyclin E, orchestrates chromatin modifiers in the DNA damage response, controls circadian BMAL1 turnover, and suppresses a noncanonical type I interferon response redundantly with SUMO3 [#3, #6, #10, #14, #19, #21]. Removal of SUMO2/3 is carried out by isoform-selective SENP/Ulp proteases (SENP3, SENP6, SENP7, SUSP1), whose structures reveal a SENP6/7 Loop1 insertion that confers poly-SUMO2 chain specificity and whose deconjugation activity feeds into proliferation, centromere maintenance, and inflammatory and osteoclast signaling [#4, #8, #21, #27, #28, #20, #22]. SUMO2 is the essential, predominant embryonic SUMO isoform\\u2014Sumo2-null mice die at ~E10.5 while Sumo3-null mice are viable\\u2014and conditional neuronal loss impairs hippocampal LTP and memory, establishing physiological roles in development and synaptic plasticity [#13, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the defining biochemical property distinguishing SUMO2 from SUMO1\\u2014its capacity to form polymeric chains\\u2014answering how a single modifier could generate higher-order signals.\",\n      \"evidence\": \"In vitro conjugation with purified SAE1/SAE2 and Ubc9 plus in vivo chain detection\",\n      \"pmids\": [\"11451954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which E3 ligases catalyze chain formation in vivo\", \"Did not establish functional consequences of chains\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved the SUMO2 fold and identified C-terminal surface charge differences from SUMO1 as a structural basis for paralog-specific behavior.\",\n      \"evidence\": \"X-ray crystallography of human SUMO-2 at 1.2 \\u00c5 with comparison to SUMO-1\",\n      \"pmids\": [\"15479240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural correlate of distinct localization inferred, not demonstrated\", \"No bound partner in the structure\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined how SUMO2 is recognized non-covalently, showing a SIM beta-strand engages SUMO2 with flanking acidic/phosphorylated residues encoding paralog selectivity.\",\n      \"evidence\": \"Yeast two-hybrid, bioinformatics and NMR mapping of SIM-SUMO2 interface\",\n      \"pmids\": [\"16524884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity rules derived from limited SIM set\", \"In vivo functional impact of paralog discrimination not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected SUMO2 chains to a specific cellular process by identifying PIASy as the E3 driving Topoisomerase-II SUMO2 conjugation required for sister chromatid segregation.\",\n      \"evidence\": \"Immunodepletion and chromatin assays in Xenopus egg extracts with PIASy mutants\",\n      \"pmids\": [\"15933717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SUMO2-TopoII enables segregation not fully resolved\", \"Mammalian validation not in this study\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated a complete mitotic SUMO2/3 conjugation-deconjugation cycle on Borealin, defining RanBP2 as writer and SENP3 as eraser for a CPC substrate.\",\n      \"evidence\": \"Co-IP, in vitro SUMOylation, siRNA and cell synchronization\",\n      \"pmids\": [\"18946085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Borealin SUMO2/3 cycling for CPC activity not fully defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked SUMO2/3 to circadian timing and to coupled degradation, showing poly-SUMO2/3 of BMAL1 promotes transactivation and proteasomal turnover at PML bodies.\",\n      \"evidence\": \"Site-directed mutagenesis (K259), co-IP, proteasome inhibition, SUSP1 manipulation\",\n      \"pmids\": [\"18644859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the BMAL1 E3 ligase not established\", \"Ubiquitin ligase coupling SUMO to degradation not named here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified a SUMO2/3-selective protease (SUSP1) acting on poly-SUMO2/3 substrates, establishing chain-length-selective deconjugation and PML-body homeostasis.\",\n      \"evidence\": \"Vinyl sulfone inhibitors, model substrate assays, siRNA and EGFP-SUMO imaging\",\n      \"pmids\": [\"17000875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous physiological substrates not defined\", \"Mechanism of chain-length preference structurally unexplained at the time\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the SUMO2 acceptor-site code and phospho-cross-talk through proteome-scale site mapping, revealing canonical and non-canonical motifs.\",\n      \"evidence\": \"Site-specific MS proteomics using engineered trypsin-cleavable SUMO-2\",\n      \"pmids\": [\"20797634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional importance of each site not tested\", \"HCSM and inverted-motif recognition determinants unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Tied SENP3-driven SUMO2/3 removal from PML to proliferation control under oxidative stress, showing SUMOylated PML is antiproliferative.\",\n      \"evidence\": \"SENP3 siRNA, reconstitution with SUMO-deficient PML, proliferation and colocalization assays\",\n      \"pmids\": [\"20181954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream proliferative effectors of PML deSUMOylation not delineated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established a SUMO2/3 brake on DNA replication by showing cyclin E is the predominant chromatin SUMO2/3 target limiting origin firing in early S phase.\",\n      \"evidence\": \"Xenopus cell-free replication, immunodepletion, chromatin fractionation, SUMO inhibition\",\n      \"pmids\": [\"23673635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase for chromatin cyclin E SUMO2/3 not identified\", \"Molecular link from cyclin E SUMOylation to origin licensing unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Implicated SUMO2 in proteostasis of disease aggregates, identifying PIAS1 as an E3 modulating mutant huntingtin solubility.\",\n      \"evidence\": \"E3 ligase screen, in vitro SUMOylation, insoluble fraction analysis, PIAS1 manipulation\",\n      \"pmids\": [\"23871671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab screen without reciprocal in vivo validation\", \"Direct link to clearance machinery not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Scaled SUMO2 site mapping to >1000 lysines, enabling systematic dissection of cell cycle, transcription and DNA repair substrates.\",\n      \"evidence\": \"His6-SUMO2(T90K) with Lys-C diGly remnant IP and MS\",\n      \"pmids\": [\"24782567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences of most sites untested\", \"E3/protease assignments per-site not made\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed SUMO2/3 conjugation acts as a phospho-gated apoptotic switch on DBC1, with ATM/ATR phosphorylation steering DBC1 from SENP1 to PIAS3 to release p53.\",\n      \"evidence\": \"Co-IP, PIAS3/SENP1/SUMO2/3 knockdowns, SUMO-deficient DBC1 mutant, etoposide and apoptosis assays\",\n      \"pmids\": [\"25406032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the phospho-switch in ligase/protease choice not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked SUMO2/3 to replication-coupled chromatin assembly via direct CAF-1 p150 SIM binding that recruits SUMO2/3 to replication foci.\",\n      \"evidence\": \"Co-IP, p150 residue 98-105 mutagenesis, siRNA, replication-foci immunofluorescence\",\n      \"pmids\": [\"19919826\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the SUMO2/3-modified target at foci not pinned down here\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined substrate-specific SUMO2 outcomes in the DDR\\u2014degradation of JARID1B via RNF4 versus chromatin recruitment of JARID1C\\u2014showing SUMO can route substrates to opposite fates.\",\n      \"evidence\": \"Quantitative SILAC SUMO-2 proteomics, siRNA, chromatin fractionation, ubiquitylation assays\",\n      \"pmids\": [\"25772364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting degradation versus recruitment unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected SUMO2 to conformational quality control, showing Hsp27/Ubc9 conjugate SUMO2 to misfolded CFTR NBD1 for RNF4-dependent degradation.\",\n      \"evidence\": \"In vitro SUMOylation with purified components, K447R mutagenesis, Hsp27 co-IP, proteasome assays\",\n      \"pmids\": [\"26627832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Hsp27 selects SUMO2 over other paralogs mechanistically unresolved\", \"In-cell relevance for F508del trafficking not fully established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Added ZNF451-1 as a SUMO2/3-specific E3 that fine-tunes PML levels cooperatively with RNF4.\",\n      \"evidence\": \"In vitro SUMOylation, E3 mechanism mutants, RNAi and PML body quantification\",\n      \"pmids\": [\"27343429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab; in vivo physiological role of ZNF451-1 not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a non-conjugative SUMO2 function, showing SUMO2 directly binds calcineurin A to drive its nuclear localization and cardiac hypertrophy independent of conjugation.\",\n      \"evidence\": \"cDNA screen, NFAT reporter, SUMO2-\\u0394GG mutant, AAV9 in vivo cardiac expression, co-IP\",\n      \"pmids\": [\"27767176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab; structural basis of the conjugation-independent interaction not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established the structural and regulatory features of SUMO2 chains, defining K11 acetylation (erased by SIRT1) as a topology modulator restricting chain length and shifting linkage usage.\",\n      \"evidence\": \"In vitro chain assays with acetyl-mimic SUMO2, MS chain-linkage proteomics, SIRT1 identification\",\n      \"pmids\": [\"30201799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Writer of SUMO2 K11 acetylation not identified\", \"Physiological contexts of acetylation-controlled topology untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a paralog-specific SUMO2-PCNA signal generated by RECQ5 that recruits CAF1/FACT to resolve transcription-replication conflicts.\",\n      \"evidence\": \"Proteomics of SUMO2-PCNA complexes, SIM-dependent interaction and histone deposition assays, ChIP, DSB quantification\",\n      \"pmids\": [\"30006506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase generating SUMO2-PCNA on transcribed chromatin not named\", \"Why SUMO2 but not SUMO3 is selected unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated redundant, paralog-specific suppression of innate immunity, with SUMO2/3 loss triggering a noncanonical IFN response independent of IRF3/IRF7.\",\n      \"evidence\": \"SUMO2/SUMO3 knockouts and IRF3/IRF7 double-knockout epistasis with IFN readouts\",\n      \"pmids\": [\"29891701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The noncanonical IFN-inducing sensor/pathway not identified\", \"Relevant SUMO2/3 substrates suppressing IFN unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed SUMO2/3 deconjugation within inflammatory signaling, showing SENP3-mediated MKK7 deSUMOylation enhances JNK/TLR4 signaling in macrophages.\",\n      \"evidence\": \"Conditional SENP3 KO mice, LPS assays, JNK phosphorylation, MKK7-JNK co-IP, septic shock model\",\n      \"pmids\": [\"29352108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MKK7 SUMO acceptor site and writer E3 not defined here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked SUMO2/3 to centrosome-cycle control via cell-cycle-resolved ATF5 SUMOylation that dislodges ATF5 from the centrosome.\",\n      \"evidence\": \"Cell synchronization, centrosomal co-IP, SUMO-deficient ATF5 mutant, genomic instability assays\",\n      \"pmids\": [\"29326161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab; E3/protease controlling ATF5 cycling not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Proposed a cytoplasmic, non-degradative SUMO2 role in cap-dependent translation by promoting eIF4E-eIF4G assembly.\",\n      \"evidence\": \"eIF4E-eIF4G co-IP, SUMO2 overexpression/knockdown, 4EGI-1 rescue, polysome profiling\",\n      \"pmids\": [\"24971752\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP with partial follow-up, not independently replicated\", \"Whether SUMO2 acts via conjugation unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a proteolysis-independent role for SUMO2/3 chains in centromere assembly, with SENP6 group-deSUMOylating the CCAN to maintain CENP loading.\",\n      \"evidence\": \"SENP6 knockdown proteomics, cell cycle analysis, centromere immunofluorescence, proteasome inhibitor controls\",\n      \"pmids\": [\"31485003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SUMO chains stabilize CCAN without triggering degradation mechanistically unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended SUMO2-RNF4 clearance to neurodegenerative aggregates, showing SUMO2/3-RNF4 promotes polyQ-ataxin-7 degradation.\",\n      \"evidence\": \"Co-IP, PLA, RNF4/SUMO2 overexpression, SCA7 knockin mouse\",\n      \"pmids\": [\"30559154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 SUMO ligase for ATXN7 not identified\", \"Therapeutic relevance untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the structural basis for SUMO2 maturation/deconjugation by SENP1 via the C-terminal QQTGG motif engaging the catalytic triad.\",\n      \"evidence\": \"X-ray crystallography of SENP1-SUMO2 noncovalent complex at 2.62 \\u00c5\",\n      \"pmids\": [\"31045562\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional mutagenesis validation in this study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a physiological osteoclast role for SUMO2/3 deconjugation, with SENP3 removing SUMO3 from IRF8 to permit NFATc1-driven osteoclastogenesis.\",\n      \"evidence\": \"Myeloid-specific SENP3 KO mice, co-IP, K310 mutagenesis, ovariectomy bone-loss model\",\n      \"pmids\": [\"32049023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Writer E3 for IRF8 SUMO3 not defined\", \"Mechanism by which IRF8 SUMOylation limits NFATc1 not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated SUMO2's physiological requirement in the nervous system, with conditional neuronal loss impairing LTP and memory absent transcriptional/morphological changes.\",\n      \"evidence\": \"Forebrain-specific Sumo2 KO mice, behavioral tests, LTP electrophysiology\",\n      \"pmids\": [\"32910521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Synaptic SUMO2 substrates mediating plasticity not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided the definitive structural explanation for SENP6/7 poly-SUMO2 specificity via a unique Loop1 insertion contacting SUMO2.\",\n      \"evidence\": \"Crystal structure of SENP7-SUMO2 with SENP2-Loop1 chimera comparison\",\n      \"pmids\": [\"36334780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chain-disassembly processivity mechanism not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified \\u03b3-actin as a cardioprotective SUMO2 substrate whose modification at K68/K284 promotes nuclear deposition and DNA-damage repair.\",\n      \"evidence\": \"Strep-SUMO2 affinity MS, K68R/K284R mutagenesis, MI and hypoxia-reoxygenation models\",\n      \"pmids\": [\"35864967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3/protease for \\u03b3-actin SUMO2 not identified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed metabolic regulation of SUMO2 itself, with ferroptosis-induced K11 lactylation impairing SUMO2-ACSL4 interaction to remodel lipid metabolism.\",\n      \"evidence\": \"SUMOylation proteomics, co-IP, metabolomics, AARS1/HDAC1 writer-eraser identification, xenografts\",\n      \"pmids\": [\"41057295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay of K11 lactylation with K11 acetylation not reconciled\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The sensor and substrates underlying SUMO2/3-mediated suppression of noncanonical type I interferon, and the determinants that route a SUMO2-modified substrate toward degradation, recruitment, or non-degradative stabilization, remain unresolved.\",\n      \"evidence\": \"Open question synthesized across DDR, immune, and proteostasis findings\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No identified IFN-inducing sensor for SUMO2/3 loss\", \"No general rule predicting SUMO2-driven substrate fate\", \"E3 assignments missing for many physiological substrates\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0031386\", \"supporting_discovery_ids\": [0, 7, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 12, 14, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 7, 11]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [30]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3, 10, 21]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [24, 36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 5, 10, 21, 31]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [12, 14, 17]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [14, 17, 26]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [14, 15, 32]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19, 20, 22]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"PML nuclear body\", \"constitutive centromere-associated network (CCAN)\", \"chromosomal passenger complex\"],\n    \"partners\": [\"UBE2I\", \"PIAS4\", \"RNF4\", \"SENP3\", \"SENP6\", \"SENP7\", \"PCNA\", \"BMAL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}