{"gene":"SUMO1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1998,"finding":"SUMO-1 conjugates IκBα primarily at K21 (the same lysine used for ubiquitin modification), preventing ubiquitination of IκBα and thus protecting it from proteasome-mediated degradation, thereby inhibiting NF-κB activation. In the presence of E1 activating enzyme, Ubc9 (E2) conjugates SUMO-1 to IκBα; SUMO-1 modification is inhibited by phosphorylation whereas ubiquitination requires it.","method":"In vitro SUMOylation assay with E1 and Ubc9; site-directed mutagenesis (K21); overexpression in cells; NF-κB reporter assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, mutagenesis, and cell-based functional readout in a single rigorous study; widely replicated by subsequent work","pmids":["9734360"],"is_preprint":false},{"year":1998,"finding":"SUMO-1 modification of RanGAP1 at K526 (via C-terminal cleavage exposing G97 as the attachment point) directs RanGAP1 to the nuclear envelope/nuclear pore complex by creating or exposing a binding site for the nucleoporin Nup358/RanBP2. Unmodified RanGAP1 is cytoplasmic; SUMO-1-modified RanGAP1 stably associates with the NE through many import cycles.","method":"Peptide mapping, mass spectrometry, site-directed mutagenesis (K526R), in vitro import assays, cell fractionation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (MS, mutagenesis, in vitro reconstitution, localization), replicated by multiple independent labs","pmids":["9442102","9456312"],"is_preprint":false},{"year":1998,"finding":"Ubc9 (Xenopus p18Ubc9) functions as the E2 conjugating enzyme specifically for SUMO-1 but not for ubiquitin, and physically interacts with RanBP2 (via its internal repeat domain, which is itself a SUMO-1 substrate in Xenopus egg extracts). SUMO-1 conjugation promotes RanGAP1 interaction with RanBP2.","method":"In vitro E2 activity assay distinguishing ubiquitin vs SUMO-1; co-immunoprecipitation; Xenopus egg extract SUMOylation assay","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution with E2 specificity assay; replicated across multiple labs","pmids":["9427648"],"is_preprint":false},{"year":1999,"finding":"In vitro SUMO-1 modification requires only two enzymatic steps (E1 activating enzyme Sua1p/hUba2 heterodimer + E2 Ubc9), unlike ubiquitin which typically requires three. hUba2 forms a thioester bond with SUMO-1; the Sua1p/Uba2p complex has E1 activity sufficient to allow Ubc9-dependent modification of RanGAP1.","method":"In vitro reconstitution with recombinant E1 (Sua1p/hUba2p) and E2 (Ubc9); biochemical thioester assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — fully reconstituted in vitro system with recombinant proteins; replicated by multiple subsequent studies","pmids":["9920803"],"is_preprint":false},{"year":1999,"finding":"p53 is modified by SUMO-1 at a single site (K386) in vitro (requiring only SUMO-1, E1, and Ubc9) and in vivo. SUMO-1 and ubiquitin modification do not compete for the same lysine in p53. Overexpression of SUMO-1 activates p53 transcriptional activity in a K386-dependent manner.","method":"In vitro SUMOylation assay; site-directed mutagenesis (K386R); transactivation reporter assay in cells; immunoprecipitation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution plus mutagenesis plus functional assay; independently replicated","pmids":["10562557","10562558","10788439"],"is_preprint":false},{"year":2000,"finding":"SUMO-1 conjugation requires a transferable PsiKXE consensus motif (where Psi is a large hydrophobic residue). Short peptide sequences from p53 and IκBα containing this motif confer SUMO-1 modification on a carrier protein in vitro, but in vivo modification additionally requires nuclear targeting (nuclear localization signal).","method":"Domain-swap/peptide-transfer in vitro and in vivo SUMOylation assays; mutagenesis; nuclear localization signal addition/removal experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution plus systematic mutagenesis, multiple substrates, in vitro and in vivo convergence","pmids":["11124955"],"is_preprint":false},{"year":1997,"finding":"PML and Sp100, components of nuclear dots/PML nuclear bodies, are covalently modified by PIC1/SUMO-1 in vivo (but not when synthesized in vitro). SUMO-1-modified Sp100 isoforms are exclusively nuclear, whereas unmodified Sp100 is also cytoplasmic, indicating that SUMO-1 modification correlates with nuclear retention of Sp100.","method":"Immunoblotting with SUMO-1-specific antibody; cell fractionation; immunofluorescence colocalization","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation and immunoblotting in stably transfected and endogenous cells; single lab but multiple orthogonal approaches","pmids":["9412458"],"is_preprint":false},{"year":1999,"finding":"SUMO-1 modification of PML at K487/K490 (within its nuclear localization signal region) is mediated by UBC9 binding to PML's RING finger domain. The SUMO-1 modification of PML-RARα fusion protein leads to SUMO-1-dependent degradation of PML-RARα in vitro.","method":"In vitro and in vivo SUMOylation assay; site-directed mutagenesis; yeast two-hybrid (UBC9-PML interaction); immunoprecipitation","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution and mutagenesis in single lab; functional consequence (degradation) shown in vitro","pmids":["9885291"],"is_preprint":false},{"year":2000,"finding":"PML is required for proper formation of PML nuclear bodies; SUMO-1 conjugation of PML is a prerequisite for this function. In primary PML−/− cells, nuclear body proteins (Sp100, CBP, ISG20, Daxx, SUMO-1) fail to accumulate in nuclear bodies and are mislocalized. A SUMO-1-conjugation-deficient PML mutant cannot restore nuclear body formation.","method":"PML−/− primary cells; re-expression of wild-type vs. SUMO-conjugation-deficient PML mutant; immunofluorescence localization of nuclear body components","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null cells complemented with wild-type vs. SUMO-deficient mutant; multiple nuclear body markers assessed; independently supported by other studies","pmids":["10779416"],"is_preprint":false},{"year":2000,"finding":"Mdm2 is SUMOylated at K446 within its RING finger domain. SUMO-1 modification prevents Mdm2 self-ubiquitination and increases its E3 ligase activity toward p53 in vitro. A K446R mutant that cannot be SUMOylated is more stable but causes increased p53 degradation and inhibits p53-mediated apoptosis. DNA damage (radiation) decreases Mdm2 SUMOylation, inversely correlating with p53 levels.","method":"In vitro SUMOylation and ubiquitination assays; site-directed mutagenesis (K446R); apoptosis assay; immunoprecipitation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution, mutagenesis, and cellular functional readout in single rigorous study","pmids":["10892746"],"is_preprint":false},{"year":2000,"finding":"Androgen receptor (AR) is SUMOylated in an androgen-enhanced fashion at consensus PsiKXE motifs in its N-terminal domain. Mutation of the SUMOylated lysines enhances AR transcriptional activity without affecting its transrepressing activity, indicating that SUMO-1 modification negatively regulates AR transactivation.","method":"In vivo SUMOylation assay; site-directed mutagenesis; transactivation reporter assay; co-immunoprecipitation with Ubc9","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis plus functional assay; ligand-dependence mechanistically characterized; replicated for related steroid receptors","pmids":["11121022"],"is_preprint":false},{"year":2000,"finding":"c-Jun is modified by SUMO-1 at K229. JNK phosphorylation of c-Jun at S63/S73 inhibits SUMO-1 modification; a K229R mutant shows increased transactivation on AP-1-containing promoters, indicating SUMO-1 negatively regulates c-Jun activity. SUMO-1 modification of p53 is similarly inhibited by phosphorylation but is unaffected by Mdm2-mediated ubiquitination.","method":"In vitro and in vivo SUMOylation; site-directed mutagenesis; transactivation reporter assays; JNK activation experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution, mutagenesis, and functional reporter assays; crosstalk with phosphorylation systematically established","pmids":["10788439"],"is_preprint":false},{"year":2000,"finding":"SUMO-1 modification of SUMO-2/3-vs-SUMO-1 substrates is functionally distinct: SUMO-2 and SUMO-3 conjugation to high-molecular-mass proteins is induced by protein-damaging stress (heat shock), whereas RanGAP1 is conjugated preferentially by SUMO-1 (not SUMO-2/3), demonstrating paralogue-specific substrate preferences.","method":"Paralogue-specific antibody; immunoblotting; heat-shock and stress treatments; comparison of SUMO-1 vs SUMO-2/3 modification of RanGAP1","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel antibody-based distinction of paralogues; single lab, two orthogonal approaches","pmids":["10692421"],"is_preprint":false},{"year":2000,"finding":"SUMO-1 conjugation targets topoisomerase I (TOP1) in response to camptothecin (CPT)-induced DNA damage in both mammalian and yeast cells expressing human TOP1. This modification depends on UBC9; TOP1 physically interacts with UBC9. UBC9 mutant yeast expressing human TOP1 are hypersensitive to CPT, implicating UBC9/SUMO-1 in repair of TOP1-mediated DNA damage.","method":"Immunoblotting with SUMO-1/Smt3p antibodies; co-immunoprecipitation (TOP1–UBC9); genetic epistasis (ubc9 mutant yeast + CPT sensitivity)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cross-species validation, genetic epistasis, and physical interaction; single lab","pmids":["10759568"],"is_preprint":false},{"year":2000,"finding":"SUMO-1 conjugation to DNA topoisomerase IIα and IIβ is induced by topoisomerase II-mediated DNA damage (VM-26) and also by ICRF-193 (which traps topoisomerase II in a clamp conformation without causing DNA strand breaks), suggesting the modification responds to protein conformational change rather than only DNA damage.","method":"Immunological characterization (anti-SUMO-1 and anti-topoII blotting); co-immunoprecipitation; drug treatment of HeLa cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal immunoprecipitation; physical interaction with SUMO-1/UBC9 shown; single lab","pmids":["10862613"],"is_preprint":false},{"year":2001,"finding":"Heat shock factor 1 (HSF1) undergoes stress-induced SUMO-1 modification at K298. SUMO-1 modification converts HSF1 to its DNA-binding form in a reconstituted in vitro SUMO-1 reaction. Mutation K298R prevents HSF1 colocalization with SUMO-1 in nuclear stress granules and reduces stress-induced transcriptional activity.","method":"In vitro reconstituted SUMO-1 modification assay; supershift EMSA with anti-SUMO-1; site-directed mutagenesis (K298R); immunofluorescence colocalization; transactivation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution converting HSF1 to DNA-binding form, mutagenesis, and functional assay; single lab","pmids":["11514557"],"is_preprint":false},{"year":2002,"finding":"SUMO-1 modification of Sp3 at acceptor lysines represses its transcriptional activation and relocalizes it to the nuclear periphery and nuclear dots. Expression of SUMO-1 protease SuPr-1, or mutation of SUMO acceptor lysines, converts Sp3 to a strong activator with diffuse nuclear distribution. Covalent gene fusion of SUMO-1 to Sp3 is sufficient to repress transcription and drive nuclear peripheral/dot localization.","method":"Site-directed mutagenesis; SUMO-1 protease (SuPr-1) expression; SUMO-1–Sp3 fusion construct; transactivation reporter assay; immunofluorescence","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — gain-of-function fusion and loss-of-function mutagenesis with functional and localization readouts; multiple orthogonal approaches in one study","pmids":["12419227"],"is_preprint":false},{"year":2002,"finding":"The SUMO-1 protease SuPr-1 hydrolyzes SUMO-1-modified PML and redistributes PML from PML nuclear bodies (PODs), as well as other POD-associated proteins (CBP, Daxx). SuPr-1-dependent activation of c-Jun transcription requires PML and is lost in PML-deficient fibroblasts, placing SUMO-1 deconjugation from PML in the transcriptional regulatory pathway.","method":"SUMO-1 hydrolase activity assay; immunofluorescence (PML redistribution); transcription reporter; PML−/− fibroblasts (genetic epistasis)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — enzymatic activity demonstrated, genetic epistasis in PML-null cells, multiple target proteins assessed","pmids":["12419228"],"is_preprint":false},{"year":2002,"finding":"SENP2 (a SUMO-1 protease) associates with the nucleoplasmic face of nuclear pores by binding Nup153 via its N-terminal domain. Deletion of the Nup153-interacting region of SENP2 significantly alters the spectrum of SUMO-1 conjugates in the cell, indicating that pore association restricts SENP2 activity to a subset of nuclear SUMO-1 conjugates.","method":"Localization by transfection/imaging; co-immunoprecipitation (SENP2–Nup153); deletion mutagenesis; immunoblotting of SUMO-1 conjugates after SENP2 domain removal","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization and binding partner identified, functional consequence of domain deletion shown; single lab","pmids":["11896061"],"is_preprint":false},{"year":2002,"finding":"HDAC1 is SUMOylated in vitro and in vivo at C-terminal K444 and K476. Mutation of these residues profoundly reduces HDAC1-mediated transcriptional repression, and eliminates HDAC1-induced cell cycle and apoptotic responses upon overexpression, without affecting HDAC1 association with mSin3A.","method":"In vitro and in vivo SUMOylation assays; site-directed mutagenesis (K444R/K476R); transcriptional reporter assay; co-immunoprecipitation with mSin3A; cell cycle/apoptosis assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution, mutagenesis, and multiple functional readouts (transcription, cell cycle, apoptosis) in one study","pmids":["11960997"],"is_preprint":false},{"year":2002,"finding":"SUMO-1 targets RanGAP1 to kinetochores and mitotic spindles. RanGAP1 associates with mitotic spindles and concentrates near kinetochores from nuclear envelope breakdown until late anaphase. A SUMO-1-conjugation-deficient RanGAP1 mutant fails to associate with spindles; RanBP2 co-localizes with RanGAP1 on spindles, suggesting a RanGAP1–SUMO-1–RanBP2 complex mediates mitotic targeting.","method":"Immunofluorescence; SUMO-1-deficient RanGAP1 mutant expression; colocalization with RanBP2 during mitosis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutant unable to be SUMOylated loses mitotic localization; colocalization with partner; replicated across studies","pmids":["11854305"],"is_preprint":false},{"year":2003,"finding":"SUMO-1/Ubc9 promotes nuclear accumulation and metabolic stability of Smad4. SUMO-1 overexpression increases Smad4 levels and nuclear localization, enhancing TGF-β transcriptional responses; Ubc9 siRNA knockdown has the opposite effect. SUMO-1 modification of Smad4 protects it from ubiquitin-dependent proteasomal degradation.","method":"Overexpression and siRNA knockdown of Ubc9/SUMO-1; subcellular fractionation; ubiquitination and half-life assays; transcriptional reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain and loss of function with matching phenotypes, ubiquitination/stability assays; multiple orthogonal methods","pmids":["12813045"],"is_preprint":false},{"year":2004,"finding":"SUMO-1 conjugates DRP1 (dynamin-related protein 1) and numerous mitochondrial outer-membrane proteins; Ubc9 and SUMO-1 are specific DRP1-interacting proteins. YFP:SUMO-1 localizes to sites of mitochondrial fission and the tips of fragmented mitochondria. SUMO-1 overexpression stabilizes DRP1 from degradation, resulting in increased mitochondrial fragmentation.","method":"Co-immunoprecipitation (SUMO1/Ubc9–DRP1); video microscopy of YFP:SUMO1 at fission sites; mitochondrial fractionation; SUMOylation assay; DRP1 stability assay","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — live-cell imaging at fission sites, co-IP, fractionation, and stability assay in single study; novel subcellular function established","pmids":["14972687"],"is_preprint":false},{"year":2004,"finding":"SUMO-1 modification of GATA4 at K366 (mediated by E3 ligase PIAS1 via its RING finger domain) enhances GATA4 transcriptional activity and promotes GATA4 nuclear occupation. SUMO-1/PIAS1 together trigger activation of cardiogenic genes in pluripotent 10T1/2 fibroblasts.","method":"In vitro and in vivo SUMOylation assays; site-directed mutagenesis (K366R); transactivation reporter assay; nuclear localization imaging; cardiogenic gene activation in 10T1/2 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis and E3 ligase identified; functional cellular assay; single lab","pmids":["15337742"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of the central region of human TDG conjugated to SUMO-1 at 2.1 Å resolution reveals a helix protruding from the protein surface that interferes with product DNA, promoting TDG dissociation from the abasic site after base excision. Both covalent attachment and non-covalent SUMO-1–TDG contacts (validated by mutagenesis) are required for DNA release.","method":"X-ray crystallography (2.1 Å); site-directed mutagenesis of non-covalent SUMO-1–TDG interface; DNA-binding/release assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure plus mutagenesis validating functional non-covalent interface; single rigorously executed study","pmids":["15959518"],"is_preprint":false},{"year":2005,"finding":"XPC protein is modified by both SUMO-1 and ubiquitin following UV irradiation in human fibroblasts, and these modifications require DDB2 and XPA. SUMO-1 modification of XPC protects it from degradation; in XP-A cells where XPC SUMOylation does not occur, XPC is significantly degraded after UV.","method":"Reciprocal immunoprecipitation; siRNA knockdown of SUMO-1; NER-deficient cell lines (XP-A, XP-C, XP-E); proteasome inhibitor treatment","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal IP, genetic requirement shown using NER-deficient lines; single lab","pmids":["16030353"],"is_preprint":false},{"year":2006,"finding":"SUMO-interacting motifs (SIMs) form a beta-strand that binds SUMO-1 or SUMO-2 in parallel or antiparallel orientation relative to the β2-strand of SUMO. A stretch of acidic amino acids and/or phosphorylated serine residues flanking the SIM determines paralogue specificity (SUMO-1 vs SUMO-2) and can modulate spatial orientation of the interaction.","method":"Yeast two-hybrid screen; bioinformatics; NMR spectroscopy mapping of SIM binding surface on SUMO-1 and SUMO-2","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural mapping plus yeast two-hybrid; mechanistic basis of SUMO-paralogue specificity defined; single lab","pmids":["16524884"],"is_preprint":false},{"year":2006,"finding":"SUMO-1 modification of DJ-1 at K130 (promoted by PIASxα or PIASy) is required for all DJ-1 functions including ras-dependent transformation, cell growth promotion, and anti-UV-induced apoptosis. Parkinson's disease-associated mutant DJ-1 L166P is improperly SUMOylated, becomes insoluble, mislocalizes to mitochondria, and is degraded by the proteasome.","method":"In vivo SUMOylation assay; site-directed mutagenesis (K130R); functional assays (transformation, cell growth, apoptosis); subcellular localization; proteasome inhibitor treatment","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with multiple functional readouts; E3 ligase identified; single lab","pmids":["15976810"],"is_preprint":false},{"year":2006,"finding":"Phosducin is SUMOylated at K33 in a consensus PsiKXE motif; SUMOylation protects phosducin from proteasomal degradation (K33R mutant has decreased stability and increased ubiquitination). SUMO-1 modification of phosducin decreases its ability to bind Gβγ subunits.","method":"In vitro and in vivo SUMOylation assays; site-directed mutagenesis (K33R); protein stability assay; ubiquitination assay; Gβγ co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus stability and binding assays; native protein from retina/heart confirmed; single lab","pmids":["16421094"],"is_preprint":false},{"year":2006,"finding":"SUMO-1 modification of SOD1 at K75 increases SOD1 steady-state levels and promotes aggregation. K75R mutation abolishes SOD1 SUMOylation; SUMO-1 co-localizes with SOD1 aggregates. The effect is observed for both wild-type and familial ALS-associated mutant SOD1.","method":"In vivo SUMOylation assay; site-directed mutagenesis (K75R); immunofluorescence colocalization; steady-state protein level assessment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis and co-localization; single lab, limited mechanistic follow-up","pmids":["16828461"],"is_preprint":false},{"year":2007,"finding":"Increased SUMO-1 modification of PML in rheumatoid arthritis synovial fibroblasts contributes to resistance to Fas-induced apoptosis by increasing recruitment of the transcriptional repressor DAXX to PML nuclear bodies. SENP1 (nuclear SUMO protease), expressed at lower levels in RA SFs, can revert this effect by releasing DAXX from PML nuclear bodies.","method":"Overexpression and knockdown experiments; immunoprecipitation; DAXX-PML NB localization assay; Fas-induced apoptosis assay; SENP1 overexpression rescue","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss of function and DAXX recruitment mechanistically linked; single lab with multiple orthogonal methods","pmids":["17360386"],"is_preprint":false},{"year":2008,"finding":"Serine 2 of the SUMO-1 N-terminal protrusion is phosphorylated in vivo, detected in human, yeast, and Drosophila cells by high-accuracy mass spectrometry, indicating an evolutionarily conserved modification of the SUMO modifier itself. SUMO-2 and SUMO-3 differ at this position; only SUMO-3 could be phosphorylated equivalently.","method":"Endogenous protein mass spectrometry (high mass accuracy MS and MS/MS, complementary fragmentation); cross-species comparison","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — high-accuracy MS with multiple fragmentation modes; single study but endogenous protein across three species","pmids":["18707152"],"is_preprint":false},{"year":2008,"finding":"In Sumo1−/− mice, SUMO-1-conjugated RanGAP1 is undetectable; however, Sumo1-null mice are viable and fertile with no developmental defects, indicating most SUMO-1 functions are compensated in vivo by SUMO-2 and SUMO-3. Expression of Sumo2 and Sumo3 mRNAs was not upregulated in Sumo1-null mice, suggesting compensation occurs at the protein modification level.","method":"Homologous recombination Sumo1 knockout; RT-PCR; immunoblotting for SUMO-1-conjugated RanGAP1 in MEFs; phenotypic analysis (viability, fertility, Mendelian ratios)","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous gene-targeted knockout with molecular confirmation (RanGAP1 conjugation absent); systematic phenotyping; single lab with high quality controls","pmids":["18573887"],"is_preprint":false},{"year":2011,"finding":"The RanBP2/RanGAP1*SUMO1/Ubc9 complex at the nuclear pore functions as a SUMO E3 ligase with specificity for SUMO1 over SUMO2. RanBP2 domain IR1 primarily provides the E3 ligase activity and protects RanGAP1-SUMO1/UBC9 from proteases; IR2 retains SUMO1-interaction that promotes SUMO1-specific E3 activity. Crystal structures of UBC9 complexed with RanGAP1-SUMO1 vs SUMO2 reveal more extensive contacts for SUMO1.","method":"Domain deletion/swap constructs; protease protection assays; automodification assays; X-ray crystal structures of UBC9–RanGAP1–SUMO1/2 complexes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures plus biochemical domain mapping; SUMO1 specificity mechanistically explained at atomic level","pmids":["22194619"],"is_preprint":false},{"year":2012,"finding":"SUMO-1 modification of PTEN at K266 (in the CBR3 loop of the C2 domain) facilitates PTEN binding to the plasma membrane through electrostatic interactions. This promotes downregulation of the PI3K/AKT pathway and suppresses anchorage-independent proliferation and tumor growth in vivo. K254 is also a minor SUMOylation site.","method":"In vivo and in vitro SUMOylation assays; site-directed mutagenesis (K266R, K254R); membrane fractionation; AKT phosphorylation assay; soft-agar and xenograft tumor assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis, membrane fractionation, and in vivo tumor suppression assay; multiple orthogonal methods; mechanistic basis (electrostatic membrane binding) established","pmids":["22713753"],"is_preprint":false},{"year":2012,"finding":"SUMO-1 occupies chromatin at promoters of actively transcribed housekeeping genes (including translation factors and ribosomal subunit genes) from G1 through late S phase but not mitosis, correlating with H3K4me3 marks. Depletion of SUMO-1 downregulates these SUMO-1-marked genes, indicating that chromatin-associated SUMO-1 positively marks and activates transcription of ribosome biogenesis and translation genes.","method":"ChIP-seq (SUMO-1 chromatin occupancy across cell cycle); SUMO-1 siRNA depletion; gene expression analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus depletion functional consequence; single lab, genome-scale but targeted functional validation","pmids":["22941651"],"is_preprint":false},{"year":2014,"finding":"CDK6 is SUMOylated by SUMO1 at K216, which blocks ubiquitination at K147, stabilizing CDK6 protein throughout the cell cycle. CDK1 phosphorylates Ubc9, which in turn mediates CDK6 SUMOylation during mitosis; CDK6 remains SUMOylated in G1 to drive G1/S transition. This SUMOylation-stabilization mechanism promotes glioblastoma progression.","method":"In vivo and in vitro SUMOylation/ubiquitination assays; site-directed mutagenesis (K216R, K147R); cell cycle synchronization; Ubc9 phosphorylation by CDK1 in vitro; CDK6 stability assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase and SUMOylation assays, mutagenesis, and cell cycle-resolved mechanism; multiple orthogonal methods","pmids":["24953629"],"is_preprint":false},{"year":2015,"finding":"Akt directly phosphorylates SUMO1 at T76, stabilizing the SUMO1 protein, and phosphorylates Ubc9 at T35, promoting Ubc9 thioester bond formation. These modifications by Akt enhance global SUMOylation and alter substrate SUMOylation specificity (STAT1, CREB), creating a mechanism by which Akt SUMOylation regulates cell proliferation through cyclin D1.","method":"In vitro kinase assays (Akt phosphorylating Ubc9 and SUMO1); site-directed mutagenesis (T35, T76); thioester bond formation assay; global SUMOylation assessment; cyclin D1/cell proliferation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis and functional readouts; single lab, multiple methods","pmids":["25867063"],"is_preprint":false},{"year":2016,"finding":"The RanBP2/RanGAP1*SUMO1/Ubc9 complex at the nuclear pore functions as an autonomous disassembly machine for Crm1-dependent nuclear export complexes, with preference for Crm1 over other exportins. Three in vitro reconstituted disassembly intermediates were characterized: Crm1 export complex binding via FG-repeat patches, cargo release by RanBP2's Ran-binding domains, and Crm1 retention after Ran-GTP hydrolysis. All intermediates are compatible with SUMO E3 ligase activity.","method":"In vitro reconstitution of disassembly intermediates with purified components; biochemical characterization of intermediates; E3 ligase activity assay in the context of export complex disassembly","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — fully reconstituted in vitro disassembly machine; multiple intermediates biochemically defined; mechanistic coupling of export and SUMOylation demonstrated","pmids":["27160050"],"is_preprint":false},{"year":2019,"finding":"PKD2 (polycystin-2) channels in arterial smooth muscle myocytes undergo triple SUMO1 modification; SUMO-PKD2 cycles between the plasma membrane and intracellular compartments. Intravascular pressure activates voltage-dependent Ca2+ influx, which promotes return of internalized SUMO-PKD2 to the plasma membrane. Reduced pressure, hyperpolarization, or Ca2+ influx inhibition causes lysosomal degradation of internalized SUMO-PKD2, reducing surface channel density. Desumoylation leads to loss of Na+ current activation and vasodilation.","method":"Inducible cell-specific Pkd2 knockout mice; biochemical SUMOylation assay; patch-clamp electrophysiology; live-cell trafficking assay; lysosomal inhibition; Ca2+ channel blockade","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-specific KO, electrophysiology, and trafficking assay; mechanistic pathway from pressure to SUMO-PKD2 surface density established with multiple orthogonal approaches","pmids":["31822608"],"is_preprint":false},{"year":2019,"finding":"NLRP3 is SUMOylated by SUMO1 at K204 (mediated by Ubc9), which facilitates ASC oligomerization and NLRP3 inflammasome activation and IL-1β secretion. SENP3 deSUMOylates NLRP3 at this site to attenuate ASC recruitment, inflammasome activation, and IL-1β cleavage.","method":"In vivo and in vitro SUMOylation assays; site-directed mutagenesis (K204R); co-immunoprecipitation (Ubc9–NLRP3); ASC oligomerization assay; IL-1β secretion assay; SENP3 overexpression/knockdown","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis, E2 interaction, functional ASC/IL-1β readouts; single lab","pmids":["31914638"],"is_preprint":false},{"year":2017,"finding":"SUMO1 modification of KHSRP at K87 (enhanced by hypoxia) inhibits its interaction with the pri-miRNA/Drosha-DGCR8 complex and promotes KHSRP translocation from nucleus to cytoplasm. This impairs processing of pre-miRNAs from pri-miRNAs that harbor short G-rich stretches in their terminal loops (TL-G-Rich miRNAs, including let-7 family), resulting in their downregulation and consequent tumorigenesis.","method":"In vivo and in vitro SUMOylation assays; site-directed mutagenesis (K87); nuclear/cytosol fractionation; co-immunoprecipitation with Drosha-DGCR8; RNA immunoprecipitation; high-throughput miRNA sequencing; xenograft tumor model","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis, fractionation, RNA-IP, and in vivo tumor model; single lab with multiple orthogonal methods","pmids":["29020972"],"is_preprint":false}],"current_model":"SUMO1 functions as a post-translational modifier that is activated by the E1 heterodimer (SAE1/SAE2/Sua1/hUba2), transferred to substrates via the sole E2 enzyme Ubc9, and often facilitated by E3 ligases (RanBP2, PIAS family), following cleavage of its C-terminal four residues to expose a diglycine motif that forms an isopeptide bond with lysine residues in a PsiKXE consensus; unlike ubiquitin, SUMO1 conjugation does not primarily target substrates for proteasomal degradation but instead regulates protein localization (directing RanGAP1 to nuclear pores/kinetochores, PML to nuclear bodies, PTEN to the plasma membrane), protein–protein interactions, transcriptional activity (repressing Sp3, c-Jun, HDAC1; activating p53, HSF1, GATA4), and protein stability (protecting IκBα, Smad4, phosducin, and CDK6 from ubiquitin-dependent degradation), with the modification reversible via SENP-family isopeptidases and crosstalk with phosphorylation and ubiquitination determining the net regulatory outcome."},"narrative":{"mechanistic_narrative":"SUMO1 is a small ubiquitin-like protein that is covalently and reversibly conjugated to lysine residues of target proteins, operating through a minimal enzymatic cascade and broadly reprogramming protein localization, stability, and transcriptional activity rather than marking substrates for degradation [PMID:9920803, PMID:11124955]. Conjugation requires only two upstream steps relative to ubiquitin: the Sua1p/hUba2 E1 heterodimer forms a SUMO1 thioester and the sole E2 enzyme Ubc9 transfers SUMO1 to substrate lysines within a transferable PsiKXE consensus motif, with in vivo modification additionally requiring nuclear targeting [PMID:9920803, PMID:11124955]. A defining functional theme is the control of subcellular localization: SUMO1 modification of RanGAP1 docks it onto the nucleoporin RanBP2/Nup358 at the nuclear pore and, during mitosis, at kinetochores and spindles [PMID:9442102, PMID:9456312, PMID:11854305], directs PTEN to the plasma membrane via electrostatic C2-domain contacts [PMID:22713753], and is required for PML to nucleate PML nuclear bodies that recruit Sp100, CBP, Daxx and other components [PMID:10779416]. SUMO1 also acts as a transcriptional rheostat—repressing Sp3, c-Jun, and HDAC1 while activating p53, HSF1, and GATA4—and is itself integrated with phosphorylation, since modification of c-Jun and p53 is antagonized by site-specific kinase activity [PMID:10788439, PMID:12419227, PMID:10562557, PMID:10562558, PMID:11514557, PMID:15337742]. A second major theme is protein stabilization through competition with ubiquitin: SUMO1 conjugation at lysines that overlap or block ubiquitination protects IkBalpha, Smad4, phosducin, and CDK6 from proteasomal turnover [PMID:9734360, PMID:12813045, PMID:16421094, PMID:24953629]. The RanBP2/RanGAP1-SUMO1/Ubc9 assembly at the pore is itself a SUMO1-specific E3 ligase and an autonomous disassembly machine for Crm1-dependent nuclear export complexes, structurally explaining SUMO1 paralogue preference [PMID:22194619, PMID:27160050]. Reversal is achieved by SENP-family isopeptidases, whose pore association (SENP2-Nup153) or expression level shapes the cellular spectrum of SUMO1 conjugates [PMID:11896061, PMID:12419228, PMID:17360386]. Gene-targeted Sumo1-null mice are viable and fertile, indicating that most SUMO1 functions are compensated at the protein level by SUMO2/3 in vivo [PMID:18573887].","teleology":[{"year":1997,"claim":"Establishing that SUMO1 is a bona fide covalent protein modifier in cells answered whether it acts like ubiquitin and linked it to nuclear retention of substrates.","evidence":"Immunoblotting, fractionation, and immunofluorescence of PML and Sp100 in cells","pmids":["9412458"],"confidence":"Medium","gaps":["Conjugation seen only in vivo, not in vitro at this stage","Acceptor lysines and enzymology unresolved"]},{"year":1998,"claim":"Identification of RanGAP1 modification and Ubc9 as a SUMO1-specific E2 defined the conjugation machinery and the prototype localization function—docking onto RanBP2 at nuclear pores.","evidence":"MS, K526R mutagenesis, in vitro import assays, E2 specificity assay, and co-IP","pmids":["9442102","9456312","9427648"],"confidence":"High","gaps":["E1 components not yet defined","How modification creates the RanBP2 binding site not structurally resolved"]},{"year":1998,"claim":"Demonstration that SUMO1 conjugates IkBalpha at the same lysine used by ubiquitin established the antagonistic, stabilizing (non-degradative) logic of SUMOylation.","evidence":"In vitro SUMOylation with E1/Ubc9, K21 mutagenesis, NF-kB reporter assays","pmids":["9734360"],"confidence":"High","gaps":["E3 ligase and in vivo stoichiometry not addressed","Generality of lysine competition unknown at the time"]},{"year":1999,"claim":"Reconstitution with the Sua1p/hUba2 E1 heterodimer plus Ubc9 showed SUMO1 needs only a two-step cascade, distinguishing it mechanistically from ubiquitin.","evidence":"In vitro reconstitution with recombinant E1/E2 and thioester assay","pmids":["9920803"],"confidence":"High","gaps":["Role and necessity of E3 ligases not yet defined","Substrate selection determinants unresolved"]},{"year":1999,"claim":"Single-site modification of p53 at K386 that activates transcription, plus PML modification at its NLS via Ubc9-RING binding, generalized SUMO1 beyond localization to direct transcriptional and substrate-fate control.","evidence":"In vitro/in vivo SUMOylation, mutagenesis (K386R), transactivation reporters, yeast two-hybrid","pmids":["10562557","10562558","9885291"],"confidence":"High","gaps":["Mechanism by which SUMO1 alters p53 transactivation not defined","Whether degradation effect on PML-RARalpha holds in vivo"]},{"year":2000,"claim":"Definition of the transferable PsiKXE consensus (with a nuclear-targeting requirement in vivo) provided the predictive rule for SUMO1 substrate recognition.","evidence":"Peptide-transfer in vitro/in vivo assays, mutagenesis, NLS manipulation","pmids":["11124955"],"confidence":"High","gaps":["Non-consensus sites not explained","How nuclear targeting couples to conjugation efficiency unresolved"]},{"year":2000,"claim":"Multiple substrates revealed SUMO1 as a transcriptional rheostat and stability switch integrated with phosphorylation—negatively regulating c-Jun and AR, modulating Mdm2/p53, and being antagonized by site-specific kinases.","evidence":"In vitro/in vivo SUMOylation, mutagenesis, transactivation and apoptosis assays, JNK activation","pmids":["10788439","11121022","10892746"],"confidence":"High","gaps":["E3 ligases for these substrates not yet identified","Quantitative crosstalk between SUMO and phospho-marks not modeled"]},{"year":2000,"claim":"PML-null complementation showed SUMO1 conjugation of PML is a prerequisite for PML nuclear body assembly, establishing SUMO1 as an organizer of a subnuclear compartment.","evidence":"PML-/- primary cells re-expressing WT vs SUMO-deficient PML; immunofluorescence of multiple NB markers","pmids":["10779416"],"confidence":"High","gaps":["Whether SUMO1 acts via covalent conjugation alone or also SIM-mediated assembly not separated","Order of recruitment of NB components unresolved"]},{"year":2000,"claim":"SUMO1-versus-SUMO2/3 paralogue-specific substrate preferences and stress-induced SUMO2/3 conjugation distinguished paralogue functions, while TOP1/TOPII modification linked SUMO1 to genotoxic and conformational stress responses.","evidence":"Paralogue-specific antibodies, heat-shock, co-IP, ubc9 yeast epistasis with camptothecin","pmids":["10692421","10759568","10862613"],"confidence":"Medium","gaps":["Acceptor lysines on topoisomerases not mapped","Functional consequence for DNA repair beyond CPT sensitivity unclear"]},{"year":2001,"claim":"Showing SUMO1 converts HSF1 to its DNA-binding form connected SUMO1 directly to activation of a stress-responsive transcription factor and to nuclear stress granules.","evidence":"Reconstituted in vitro SUMOylation, supershift EMSA, K298R mutagenesis, colocalization","pmids":["11514557"],"confidence":"High","gaps":["Stress signal that triggers HSF1 SUMOylation not defined","E3 ligase unidentified"]},{"year":2002,"claim":"Mitotic targeting of RanGAP1 to kinetochores/spindles and the SuPr-1/SENP2 deconjugation studies established the dynamic, reversible nature of SUMO1 modification and its spatial confinement at the pore.","evidence":"SUMO-deficient RanGAP1 mutant imaging, SUMO protease activity assays, SENP2-Nup153 co-IP, PML-null epistasis","pmids":["11854305","12419228","11896061","12419227","11960997"],"confidence":"High","gaps":["Substrate selectivity rules for individual SENPs incomplete","How deconjugation timing is regulated during cell cycle unresolved"]},{"year":2003,"claim":"Gain/loss-of-function on Smad4 demonstrated that SUMO1 stabilizes substrates by protecting them from ubiquitin-dependent degradation, generalizing the IkBalpha paradigm.","evidence":"Ubc9/SUMO1 overexpression and siRNA, fractionation, half-life and ubiquitination assays, TGF-beta reporter","pmids":["12813045"],"confidence":"High","gaps":["Direct acceptor lysine and E3 for Smad4 not pinned down here","Whether localization vs stability dominates the phenotype unclear"]},{"year":2004,"claim":"DRP1 modification placed SUMO1 at mitochondrial fission sites, extending its action to outer-membrane protein dynamics and organelle morphology.","evidence":"Co-IP, live YFP:SUMO1 imaging at fission sites, fractionation, DRP1 stability assay","pmids":["14972687"],"confidence":"High","gaps":["DRP1 acceptor lysine not defined","E3 ligase and physiological trigger unknown"]},{"year":2005,"claim":"The TDG-SUMO1 crystal structure provided atomic-level proof that SUMO1 can act allosterically—remodeling a substrate surface to drive DNA release—and that non-covalent SUMO contacts contribute to function.","evidence":"2.1 A X-ray structure plus interface mutagenesis and DNA-binding/release assays; XPC modification in NER-deficient lines","pmids":["15959518","16030353"],"confidence":"High","gaps":["Generality of allosteric remodeling to other substrates untested","In vivo turnover dynamics of TDG-SUMO1 not addressed"]},{"year":2006,"claim":"Defining the SIM as a beta-strand whose flanking acidic/phospho residues confer paralogue specificity explained how SUMO1 builds non-covalent interaction networks, and individual substrates (DJ-1, phosducin, SOD1) tied SUMO1 to stability and disease.","evidence":"Yeast two-hybrid, NMR mapping; substrate mutagenesis and stability/aggregation assays","pmids":["16524884","15976810","16421094","16828461"],"confidence":"Medium","gaps":["Quantitative affinity rules for SIM-SUMO1 binding incomplete","Disease-relevance (DJ-1 L166P, SOD1) shown largely in overexpression systems"]},{"year":2007,"claim":"Linking SUMO1-PML and SENP1 to DAXX recruitment and Fas-resistance in RA synovial fibroblasts connected the SUMO1 cycle to a disease-relevant apoptotic phenotype.","evidence":"Overexpression/knockdown, IP, DAXX-PML NB localization, Fas apoptosis assay, SENP1 rescue","pmids":["17360386"],"confidence":"Medium","gaps":["Causality in primary disease tissue not fully established","Single-lab observation"]},{"year":2008,"claim":"Phosphorylation of SUMO1's own N-terminal Ser2 and the viable Sumo1-null mouse established that the modifier itself is regulated and that SUMO2/3 compensate for most SUMO1 functions in vivo at the protein level.","evidence":"Endogenous MS across three species; Sumo1 knockout with RanGAP1 conjugation readout and phenotyping","pmids":["18707152","18573887"],"confidence":"High","gaps":["Functional consequence of SUMO1 Ser2 phosphorylation unknown","Mechanism of SUMO2/3 compensation at substrate level not defined"]},{"year":2011,"claim":"Crystallographic and biochemical dissection of the RanBP2/RanGAP1-SUMO1/Ubc9 complex established it as a SUMO1-specific E3 ligase and explained paralogue preference at atomic resolution.","evidence":"Domain swaps, protease-protection, automodification, X-ray structures of UBC9-RanGAP1-SUMO1/2","pmids":["22194619"],"confidence":"High","gaps":["How substrate diversity is achieved by a pore-anchored ligase unclear","Regulation of this E3 in cells not addressed"]},{"year":2012,"claim":"PTEN K266 membrane targeting and SUMO1 chromatin occupancy at housekeeping/ribosome-biogenesis promoters expanded SUMO1's roles to PI3K/AKT tumor suppression and direct transcriptional activation of growth genes.","evidence":"SUMOylation/mutagenesis, membrane fractionation, AKT and xenograft assays; ChIP-seq with SUMO1 depletion","pmids":["22713753","22941651"],"confidence":"High","gaps":["How chromatin-bound SUMO1 mechanistically activates transcription unclear","Whether PTEN membrane effect is conserved across tissues untested"]},{"year":2014,"claim":"CDK6 K216 SUMOylation blocking K147 ubiquitination, controlled by CDK1-phosphorylated Ubc9, integrated SUMO1-mediated stabilization into cell-cycle progression and glioblastoma.","evidence":"SUMOylation/ubiquitination assays, mutagenesis, cell-cycle synchronization, in vitro CDK1 kinase assay","pmids":["24953629"],"confidence":"High","gaps":["E3 ligase for CDK6 not identified","In vivo tumor dependency not fully established"]},{"year":2016,"claim":"Reconstitution of the RanBP2 complex as an autonomous Crm1 export-complex disassembly machine coupled nuclear export termination to SUMO1 E3 activity at the pore.","evidence":"In vitro reconstitution of disassembly intermediates with purified components plus E3 activity assay","pmids":["27160050"],"confidence":"High","gaps":["In-cell coordination of disassembly and SUMOylation not demonstrated","Selectivity for Crm1 over other exportins mechanism partial"]},{"year":2019,"claim":"PKD2 trafficking and NLRP3 inflammasome control demonstrated that reversible SUMO1 modification governs ion-channel surface density and innate immune signaling, with cognate SENPs reversing the effect.","evidence":"Cell-specific Pkd2 KO, patch-clamp, trafficking assays; NLRP3 mutagenesis, ASC oligomerization, IL-1beta, SENP3 modulation","pmids":["31822608","31914638"],"confidence":"High","gaps":["E3 ligases for PKD2 and NLRP3 not identified","Physiological signals coupling SUMO1 cycling to function only partly defined"]},{"year":null,"claim":"How upstream signaling kinases (e.g., Akt phosphorylating SUMO1/Ubc9) and the choice of E3 ligase combine to dictate substrate-specific SUMO1 conjugation across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying rule linking E3 ligase repertoire to substrate selection","Physiological triggers for many substrate modifications undefined","Mechanism of SUMO2/3 compensation at the substrate level unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0031386","term_label":"protein tag activity","supporting_discovery_ids":[0,1,4,5,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,9,21,28,36]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,11,16,19,23,35]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[33,38]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1,18,38]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,6,8,16,35]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[20]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[22]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[34,39]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[35]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,5,0,21,28,36]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,11,16,19,23,35]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,20,34,38,39]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[13,14,24,25]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[20,36]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,40]}],"complexes":["RanBP2/RanGAP1-SUMO1/Ubc9 E3 ligase complex","PML nuclear bodies"],"partners":["UBC9","SAE2","SAE1","RANBP2","RANGAP1","PIAS1","PML","SENP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P63165","full_name":"Small ubiquitin-related modifier 1","aliases":["GAP-modifying protein 1","GMP1","SMT3 homolog 3","Sentrin","Ubiquitin-homology domain protein PIC1","Ubiquitin-like protein SMT3C","Smt3C","Ubiquitin-like protein UBL1"],"length_aa":101,"mass_kda":11.6,"function":"Ubiquitin-like protein that can be covalently attached to proteins as a monomer or 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 E3 ligases such as PIAS1-4, RANBP2 or CBX4. 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. Involved for instance in targeting RANGAP1 to the nuclear pore complex protein RANBP2. Covalently attached to the voltage-gated potassium channel KCNB1; this modulates the gating characteristics of KCNB1 (PubMed:19223394). Polymeric SUMO1 chains are also susceptible to polyubiquitination which functions as a signal for proteasomal degradation of modified proteins. May also regulate a network of genes involved in palate development. Covalently attached to ZFHX3 (PubMed:24651376)","subcellular_location":"Nucleus membrane; Nucleus speckle; Cytoplasm; Nucleus, PML body; Cell membrane; Nucleus","url":"https://www.uniprot.org/uniprotkb/P63165/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SUMO1","classification":"Not Classified","n_dependent_lines":26,"n_total_lines":1208,"dependency_fraction":0.02152317880794702},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RAN","stoichiometry":4.0},{"gene":"RANBP2","stoichiometry":4.0},{"gene":"XPO1","stoichiometry":4.0},{"gene":"CBX1","stoichiometry":0.2},{"gene":"KPNA4","stoichiometry":0.2},{"gene":"KPNB1","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"NUTF2","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SUMO1","total_profiled":1310},"omim":[{"mim_id":"620868","title":"AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 3C; ARID3C","url":"https://www.omim.org/entry/620868"},{"mim_id":"619906","title":"DExD-BOX HELICASE 39A; DDX39A","url":"https://www.omim.org/entry/619906"},{"mim_id":"619427","title":"ZINC FINGER PROTEIN 410; ZNF410","url":"https://www.omim.org/entry/619427"},{"mim_id":"617470","title":"UBIQUITIN-SPECIFIC PEPTIDASE-LIKE 1; USPL1","url":"https://www.omim.org/entry/617470"},{"mim_id":"616910","title":"IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 3; ICF3","url":"https://www.omim.org/entry/616910"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear membrane","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SUMO1"},"hgnc":{"alias_symbol":["PIC1","GMP1","SMT3C","SUMO-1","SMT3H3","OFC10"],"prev_symbol":["UBL1"]},"alphafold":{"accession":"P63165","domains":[{"cath_id":"3.10.20.90","chopping":"20-87","consensus_level":"high","plddt":89.3175,"start":20,"end":87}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P63165","model_url":"https://alphafold.ebi.ac.uk/files/AF-P63165-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P63165-F1-predicted_aligned_error_v6.png","plddt_mean":78.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SUMO1","jax_strain_url":"https://www.jax.org/strain/search?query=SUMO1"},"sequence":{"accession":"P63165","fasta_url":"https://rest.uniprot.org/uniprotkb/P63165.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P63165/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P63165"}},"corpus_meta":[{"pmid":"9734360","id":"PMC_9734360","title":"SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation.","date":"1998","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/9734360","citation_count":930,"is_preprint":false},{"pmid":"10692421","id":"PMC_10692421","title":"Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10692421","citation_count":734,"is_preprint":false},{"pmid":"11124955","id":"PMC_11124955","title":"SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11124955","citation_count":636,"is_preprint":false},{"pmid":"10562557","id":"PMC_10562557","title":"SUMO-1 modification activates the transcriptional response of p53.","date":"1999","source":"The EMBO 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complex.","date":"1998","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9456312","citation_count":395,"is_preprint":false},{"pmid":"11121022","id":"PMC_11121022","title":"Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1).","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11121022","citation_count":367,"is_preprint":false},{"pmid":"10788439","id":"PMC_10788439","title":"c-Jun and p53 activity is modulated by SUMO-1 modification.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10788439","citation_count":344,"is_preprint":false},{"pmid":"12419227","id":"PMC_12419227","title":"SUMO-1 modification represses Sp3 transcriptional activation and modulates its subnuclear localization.","date":"2002","source":"Molecular 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In the presence of E1 activating enzyme, Ubc9 (E2) conjugates SUMO-1 to IκBα; SUMO-1 modification is inhibited by phosphorylation whereas ubiquitination requires it.\",\n      \"method\": \"In vitro SUMOylation assay with E1 and Ubc9; site-directed mutagenesis (K21); overexpression in cells; NF-κB reporter assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, mutagenesis, and cell-based functional readout in a single rigorous study; widely replicated by subsequent work\",\n      \"pmids\": [\"9734360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SUMO-1 modification of RanGAP1 at K526 (via C-terminal cleavage exposing G97 as the attachment point) directs RanGAP1 to the nuclear envelope/nuclear pore complex by creating or exposing a binding site for the nucleoporin Nup358/RanBP2. Unmodified RanGAP1 is cytoplasmic; SUMO-1-modified RanGAP1 stably associates with the NE through many import cycles.\",\n      \"method\": \"Peptide mapping, mass spectrometry, site-directed mutagenesis (K526R), in vitro import assays, cell fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (MS, mutagenesis, in vitro reconstitution, localization), replicated by multiple independent labs\",\n      \"pmids\": [\"9442102\", \"9456312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Ubc9 (Xenopus p18Ubc9) functions as the E2 conjugating enzyme specifically for SUMO-1 but not for ubiquitin, and physically interacts with RanBP2 (via its internal repeat domain, which is itself a SUMO-1 substrate in Xenopus egg extracts). SUMO-1 conjugation promotes RanGAP1 interaction with RanBP2.\",\n      \"method\": \"In vitro E2 activity assay distinguishing ubiquitin vs SUMO-1; co-immunoprecipitation; Xenopus egg extract SUMOylation assay\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution with E2 specificity assay; replicated across multiple labs\",\n      \"pmids\": [\"9427648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"In vitro SUMO-1 modification requires only two enzymatic steps (E1 activating enzyme Sua1p/hUba2 heterodimer + E2 Ubc9), unlike ubiquitin which typically requires three. hUba2 forms a thioester bond with SUMO-1; the Sua1p/Uba2p complex has E1 activity sufficient to allow Ubc9-dependent modification of RanGAP1.\",\n      \"method\": \"In vitro reconstitution with recombinant E1 (Sua1p/hUba2p) and E2 (Ubc9); biochemical thioester assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — fully reconstituted in vitro system with recombinant proteins; replicated by multiple subsequent studies\",\n      \"pmids\": [\"9920803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"p53 is modified by SUMO-1 at a single site (K386) in vitro (requiring only SUMO-1, E1, and Ubc9) and in vivo. SUMO-1 and ubiquitin modification do not compete for the same lysine in p53. Overexpression of SUMO-1 activates p53 transcriptional activity in a K386-dependent manner.\",\n      \"method\": \"In vitro SUMOylation assay; site-directed mutagenesis (K386R); transactivation reporter assay in cells; immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution plus mutagenesis plus functional assay; independently replicated\",\n      \"pmids\": [\"10562557\", \"10562558\", \"10788439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SUMO-1 conjugation requires a transferable PsiKXE consensus motif (where Psi is a large hydrophobic residue). Short peptide sequences from p53 and IκBα containing this motif confer SUMO-1 modification on a carrier protein in vitro, but in vivo modification additionally requires nuclear targeting (nuclear localization signal).\",\n      \"method\": \"Domain-swap/peptide-transfer in vitro and in vivo SUMOylation assays; mutagenesis; nuclear localization signal addition/removal experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution plus systematic mutagenesis, multiple substrates, in vitro and in vivo convergence\",\n      \"pmids\": [\"11124955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"PML and Sp100, components of nuclear dots/PML nuclear bodies, are covalently modified by PIC1/SUMO-1 in vivo (but not when synthesized in vitro). SUMO-1-modified Sp100 isoforms are exclusively nuclear, whereas unmodified Sp100 is also cytoplasmic, indicating that SUMO-1 modification correlates with nuclear retention of Sp100.\",\n      \"method\": \"Immunoblotting with SUMO-1-specific antibody; cell fractionation; immunofluorescence colocalization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation and immunoblotting in stably transfected and endogenous cells; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"9412458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SUMO-1 modification of PML at K487/K490 (within its nuclear localization signal region) is mediated by UBC9 binding to PML's RING finger domain. The SUMO-1 modification of PML-RARα fusion protein leads to SUMO-1-dependent degradation of PML-RARα in vitro.\",\n      \"method\": \"In vitro and in vivo SUMOylation assay; site-directed mutagenesis; yeast two-hybrid (UBC9-PML interaction); immunoprecipitation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution and mutagenesis in single lab; functional consequence (degradation) shown in vitro\",\n      \"pmids\": [\"9885291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PML is required for proper formation of PML nuclear bodies; SUMO-1 conjugation of PML is a prerequisite for this function. In primary PML−/− cells, nuclear body proteins (Sp100, CBP, ISG20, Daxx, SUMO-1) fail to accumulate in nuclear bodies and are mislocalized. A SUMO-1-conjugation-deficient PML mutant cannot restore nuclear body formation.\",\n      \"method\": \"PML−/− primary cells; re-expression of wild-type vs. SUMO-conjugation-deficient PML mutant; immunofluorescence localization of nuclear body components\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null cells complemented with wild-type vs. SUMO-deficient mutant; multiple nuclear body markers assessed; independently supported by other studies\",\n      \"pmids\": [\"10779416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mdm2 is SUMOylated at K446 within its RING finger domain. SUMO-1 modification prevents Mdm2 self-ubiquitination and increases its E3 ligase activity toward p53 in vitro. A K446R mutant that cannot be SUMOylated is more stable but causes increased p53 degradation and inhibits p53-mediated apoptosis. DNA damage (radiation) decreases Mdm2 SUMOylation, inversely correlating with p53 levels.\",\n      \"method\": \"In vitro SUMOylation and ubiquitination assays; site-directed mutagenesis (K446R); apoptosis assay; immunoprecipitation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution, mutagenesis, and cellular functional readout in single rigorous study\",\n      \"pmids\": [\"10892746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Androgen receptor (AR) is SUMOylated in an androgen-enhanced fashion at consensus PsiKXE motifs in its N-terminal domain. Mutation of the SUMOylated lysines enhances AR transcriptional activity without affecting its transrepressing activity, indicating that SUMO-1 modification negatively regulates AR transactivation.\",\n      \"method\": \"In vivo SUMOylation assay; site-directed mutagenesis; transactivation reporter assay; co-immunoprecipitation with Ubc9\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis plus functional assay; ligand-dependence mechanistically characterized; replicated for related steroid receptors\",\n      \"pmids\": [\"11121022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"c-Jun is modified by SUMO-1 at K229. JNK phosphorylation of c-Jun at S63/S73 inhibits SUMO-1 modification; a K229R mutant shows increased transactivation on AP-1-containing promoters, indicating SUMO-1 negatively regulates c-Jun activity. SUMO-1 modification of p53 is similarly inhibited by phosphorylation but is unaffected by Mdm2-mediated ubiquitination.\",\n      \"method\": \"In vitro and in vivo SUMOylation; site-directed mutagenesis; transactivation reporter assays; JNK activation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution, mutagenesis, and functional reporter assays; crosstalk with phosphorylation systematically established\",\n      \"pmids\": [\"10788439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SUMO-1 modification of SUMO-2/3-vs-SUMO-1 substrates is functionally distinct: SUMO-2 and SUMO-3 conjugation to high-molecular-mass proteins is induced by protein-damaging stress (heat shock), whereas RanGAP1 is conjugated preferentially by SUMO-1 (not SUMO-2/3), demonstrating paralogue-specific substrate preferences.\",\n      \"method\": \"Paralogue-specific antibody; immunoblotting; heat-shock and stress treatments; comparison of SUMO-1 vs SUMO-2/3 modification of RanGAP1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel antibody-based distinction of paralogues; single lab, two orthogonal approaches\",\n      \"pmids\": [\"10692421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SUMO-1 conjugation targets topoisomerase I (TOP1) in response to camptothecin (CPT)-induced DNA damage in both mammalian and yeast cells expressing human TOP1. This modification depends on UBC9; TOP1 physically interacts with UBC9. UBC9 mutant yeast expressing human TOP1 are hypersensitive to CPT, implicating UBC9/SUMO-1 in repair of TOP1-mediated DNA damage.\",\n      \"method\": \"Immunoblotting with SUMO-1/Smt3p antibodies; co-immunoprecipitation (TOP1–UBC9); genetic epistasis (ubc9 mutant yeast + CPT sensitivity)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cross-species validation, genetic epistasis, and physical interaction; single lab\",\n      \"pmids\": [\"10759568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SUMO-1 conjugation to DNA topoisomerase IIα and IIβ is induced by topoisomerase II-mediated DNA damage (VM-26) and also by ICRF-193 (which traps topoisomerase II in a clamp conformation without causing DNA strand breaks), suggesting the modification responds to protein conformational change rather than only DNA damage.\",\n      \"method\": \"Immunological characterization (anti-SUMO-1 and anti-topoII blotting); co-immunoprecipitation; drug treatment of HeLa cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal immunoprecipitation; physical interaction with SUMO-1/UBC9 shown; single lab\",\n      \"pmids\": [\"10862613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Heat shock factor 1 (HSF1) undergoes stress-induced SUMO-1 modification at K298. SUMO-1 modification converts HSF1 to its DNA-binding form in a reconstituted in vitro SUMO-1 reaction. Mutation K298R prevents HSF1 colocalization with SUMO-1 in nuclear stress granules and reduces stress-induced transcriptional activity.\",\n      \"method\": \"In vitro reconstituted SUMO-1 modification assay; supershift EMSA with anti-SUMO-1; site-directed mutagenesis (K298R); immunofluorescence colocalization; transactivation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution converting HSF1 to DNA-binding form, mutagenesis, and functional assay; single lab\",\n      \"pmids\": [\"11514557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SUMO-1 modification of Sp3 at acceptor lysines represses its transcriptional activation and relocalizes it to the nuclear periphery and nuclear dots. Expression of SUMO-1 protease SuPr-1, or mutation of SUMO acceptor lysines, converts Sp3 to a strong activator with diffuse nuclear distribution. Covalent gene fusion of SUMO-1 to Sp3 is sufficient to repress transcription and drive nuclear peripheral/dot localization.\",\n      \"method\": \"Site-directed mutagenesis; SUMO-1 protease (SuPr-1) expression; SUMO-1–Sp3 fusion construct; transactivation reporter assay; immunofluorescence\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — gain-of-function fusion and loss-of-function mutagenesis with functional and localization readouts; multiple orthogonal approaches in one study\",\n      \"pmids\": [\"12419227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The SUMO-1 protease SuPr-1 hydrolyzes SUMO-1-modified PML and redistributes PML from PML nuclear bodies (PODs), as well as other POD-associated proteins (CBP, Daxx). SuPr-1-dependent activation of c-Jun transcription requires PML and is lost in PML-deficient fibroblasts, placing SUMO-1 deconjugation from PML in the transcriptional regulatory pathway.\",\n      \"method\": \"SUMO-1 hydrolase activity assay; immunofluorescence (PML redistribution); transcription reporter; PML−/− fibroblasts (genetic epistasis)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — enzymatic activity demonstrated, genetic epistasis in PML-null cells, multiple target proteins assessed\",\n      \"pmids\": [\"12419228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SENP2 (a SUMO-1 protease) associates with the nucleoplasmic face of nuclear pores by binding Nup153 via its N-terminal domain. Deletion of the Nup153-interacting region of SENP2 significantly alters the spectrum of SUMO-1 conjugates in the cell, indicating that pore association restricts SENP2 activity to a subset of nuclear SUMO-1 conjugates.\",\n      \"method\": \"Localization by transfection/imaging; co-immunoprecipitation (SENP2–Nup153); deletion mutagenesis; immunoblotting of SUMO-1 conjugates after SENP2 domain removal\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization and binding partner identified, functional consequence of domain deletion shown; single lab\",\n      \"pmids\": [\"11896061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HDAC1 is SUMOylated in vitro and in vivo at C-terminal K444 and K476. Mutation of these residues profoundly reduces HDAC1-mediated transcriptional repression, and eliminates HDAC1-induced cell cycle and apoptotic responses upon overexpression, without affecting HDAC1 association with mSin3A.\",\n      \"method\": \"In vitro and in vivo SUMOylation assays; site-directed mutagenesis (K444R/K476R); transcriptional reporter assay; co-immunoprecipitation with mSin3A; cell cycle/apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution, mutagenesis, and multiple functional readouts (transcription, cell cycle, apoptosis) in one study\",\n      \"pmids\": [\"11960997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SUMO-1 targets RanGAP1 to kinetochores and mitotic spindles. RanGAP1 associates with mitotic spindles and concentrates near kinetochores from nuclear envelope breakdown until late anaphase. A SUMO-1-conjugation-deficient RanGAP1 mutant fails to associate with spindles; RanBP2 co-localizes with RanGAP1 on spindles, suggesting a RanGAP1–SUMO-1–RanBP2 complex mediates mitotic targeting.\",\n      \"method\": \"Immunofluorescence; SUMO-1-deficient RanGAP1 mutant expression; colocalization with RanBP2 during mitosis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutant unable to be SUMOylated loses mitotic localization; colocalization with partner; replicated across studies\",\n      \"pmids\": [\"11854305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SUMO-1/Ubc9 promotes nuclear accumulation and metabolic stability of Smad4. SUMO-1 overexpression increases Smad4 levels and nuclear localization, enhancing TGF-β transcriptional responses; Ubc9 siRNA knockdown has the opposite effect. SUMO-1 modification of Smad4 protects it from ubiquitin-dependent proteasomal degradation.\",\n      \"method\": \"Overexpression and siRNA knockdown of Ubc9/SUMO-1; subcellular fractionation; ubiquitination and half-life assays; transcriptional reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain and loss of function with matching phenotypes, ubiquitination/stability assays; multiple orthogonal methods\",\n      \"pmids\": [\"12813045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SUMO-1 conjugates DRP1 (dynamin-related protein 1) and numerous mitochondrial outer-membrane proteins; Ubc9 and SUMO-1 are specific DRP1-interacting proteins. YFP:SUMO-1 localizes to sites of mitochondrial fission and the tips of fragmented mitochondria. SUMO-1 overexpression stabilizes DRP1 from degradation, resulting in increased mitochondrial fragmentation.\",\n      \"method\": \"Co-immunoprecipitation (SUMO1/Ubc9–DRP1); video microscopy of YFP:SUMO1 at fission sites; mitochondrial fractionation; SUMOylation assay; DRP1 stability assay\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live-cell imaging at fission sites, co-IP, fractionation, and stability assay in single study; novel subcellular function established\",\n      \"pmids\": [\"14972687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SUMO-1 modification of GATA4 at K366 (mediated by E3 ligase PIAS1 via its RING finger domain) enhances GATA4 transcriptional activity and promotes GATA4 nuclear occupation. SUMO-1/PIAS1 together trigger activation of cardiogenic genes in pluripotent 10T1/2 fibroblasts.\",\n      \"method\": \"In vitro and in vivo SUMOylation assays; site-directed mutagenesis (K366R); transactivation reporter assay; nuclear localization imaging; cardiogenic gene activation in 10T1/2 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis and E3 ligase identified; functional cellular assay; single lab\",\n      \"pmids\": [\"15337742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of the central region of human TDG conjugated to SUMO-1 at 2.1 Å resolution reveals a helix protruding from the protein surface that interferes with product DNA, promoting TDG dissociation from the abasic site after base excision. Both covalent attachment and non-covalent SUMO-1–TDG contacts (validated by mutagenesis) are required for DNA release.\",\n      \"method\": \"X-ray crystallography (2.1 Å); site-directed mutagenesis of non-covalent SUMO-1–TDG interface; DNA-binding/release assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure plus mutagenesis validating functional non-covalent interface; single rigorously executed study\",\n      \"pmids\": [\"15959518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"XPC protein is modified by both SUMO-1 and ubiquitin following UV irradiation in human fibroblasts, and these modifications require DDB2 and XPA. SUMO-1 modification of XPC protects it from degradation; in XP-A cells where XPC SUMOylation does not occur, XPC is significantly degraded after UV.\",\n      \"method\": \"Reciprocal immunoprecipitation; siRNA knockdown of SUMO-1; NER-deficient cell lines (XP-A, XP-C, XP-E); proteasome inhibitor treatment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal IP, genetic requirement shown using NER-deficient lines; single lab\",\n      \"pmids\": [\"16030353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SUMO-interacting motifs (SIMs) form a beta-strand that binds SUMO-1 or SUMO-2 in parallel or antiparallel orientation relative to the β2-strand of SUMO. A stretch of acidic amino acids and/or phosphorylated serine residues flanking the SIM determines paralogue specificity (SUMO-1 vs SUMO-2) and can modulate spatial orientation of the interaction.\",\n      \"method\": \"Yeast two-hybrid screen; bioinformatics; NMR spectroscopy mapping of SIM binding surface on SUMO-1 and SUMO-2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural mapping plus yeast two-hybrid; mechanistic basis of SUMO-paralogue specificity defined; single lab\",\n      \"pmids\": [\"16524884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SUMO-1 modification of DJ-1 at K130 (promoted by PIASxα or PIASy) is required for all DJ-1 functions including ras-dependent transformation, cell growth promotion, and anti-UV-induced apoptosis. Parkinson's disease-associated mutant DJ-1 L166P is improperly SUMOylated, becomes insoluble, mislocalizes to mitochondria, and is degraded by the proteasome.\",\n      \"method\": \"In vivo SUMOylation assay; site-directed mutagenesis (K130R); functional assays (transformation, cell growth, apoptosis); subcellular localization; proteasome inhibitor treatment\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with multiple functional readouts; E3 ligase identified; single lab\",\n      \"pmids\": [\"15976810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Phosducin is SUMOylated at K33 in a consensus PsiKXE motif; SUMOylation protects phosducin from proteasomal degradation (K33R mutant has decreased stability and increased ubiquitination). SUMO-1 modification of phosducin decreases its ability to bind Gβγ subunits.\",\n      \"method\": \"In vitro and in vivo SUMOylation assays; site-directed mutagenesis (K33R); protein stability assay; ubiquitination assay; Gβγ co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus stability and binding assays; native protein from retina/heart confirmed; single lab\",\n      \"pmids\": [\"16421094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SUMO-1 modification of SOD1 at K75 increases SOD1 steady-state levels and promotes aggregation. K75R mutation abolishes SOD1 SUMOylation; SUMO-1 co-localizes with SOD1 aggregates. The effect is observed for both wild-type and familial ALS-associated mutant SOD1.\",\n      \"method\": \"In vivo SUMOylation assay; site-directed mutagenesis (K75R); immunofluorescence colocalization; steady-state protein level assessment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis and co-localization; single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"16828461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Increased SUMO-1 modification of PML in rheumatoid arthritis synovial fibroblasts contributes to resistance to Fas-induced apoptosis by increasing recruitment of the transcriptional repressor DAXX to PML nuclear bodies. SENP1 (nuclear SUMO protease), expressed at lower levels in RA SFs, can revert this effect by releasing DAXX from PML nuclear bodies.\",\n      \"method\": \"Overexpression and knockdown experiments; immunoprecipitation; DAXX-PML NB localization assay; Fas-induced apoptosis assay; SENP1 overexpression rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss of function and DAXX recruitment mechanistically linked; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17360386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Serine 2 of the SUMO-1 N-terminal protrusion is phosphorylated in vivo, detected in human, yeast, and Drosophila cells by high-accuracy mass spectrometry, indicating an evolutionarily conserved modification of the SUMO modifier itself. SUMO-2 and SUMO-3 differ at this position; only SUMO-3 could be phosphorylated equivalently.\",\n      \"method\": \"Endogenous protein mass spectrometry (high mass accuracy MS and MS/MS, complementary fragmentation); cross-species comparison\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-accuracy MS with multiple fragmentation modes; single study but endogenous protein across three species\",\n      \"pmids\": [\"18707152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In Sumo1−/− mice, SUMO-1-conjugated RanGAP1 is undetectable; however, Sumo1-null mice are viable and fertile with no developmental defects, indicating most SUMO-1 functions are compensated in vivo by SUMO-2 and SUMO-3. Expression of Sumo2 and Sumo3 mRNAs was not upregulated in Sumo1-null mice, suggesting compensation occurs at the protein modification level.\",\n      \"method\": \"Homologous recombination Sumo1 knockout; RT-PCR; immunoblotting for SUMO-1-conjugated RanGAP1 in MEFs; phenotypic analysis (viability, fertility, Mendelian ratios)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous gene-targeted knockout with molecular confirmation (RanGAP1 conjugation absent); systematic phenotyping; single lab with high quality controls\",\n      \"pmids\": [\"18573887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The RanBP2/RanGAP1*SUMO1/Ubc9 complex at the nuclear pore functions as a SUMO E3 ligase with specificity for SUMO1 over SUMO2. RanBP2 domain IR1 primarily provides the E3 ligase activity and protects RanGAP1-SUMO1/UBC9 from proteases; IR2 retains SUMO1-interaction that promotes SUMO1-specific E3 activity. Crystal structures of UBC9 complexed with RanGAP1-SUMO1 vs SUMO2 reveal more extensive contacts for SUMO1.\",\n      \"method\": \"Domain deletion/swap constructs; protease protection assays; automodification assays; X-ray crystal structures of UBC9–RanGAP1–SUMO1/2 complexes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures plus biochemical domain mapping; SUMO1 specificity mechanistically explained at atomic level\",\n      \"pmids\": [\"22194619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SUMO-1 modification of PTEN at K266 (in the CBR3 loop of the C2 domain) facilitates PTEN binding to the plasma membrane through electrostatic interactions. This promotes downregulation of the PI3K/AKT pathway and suppresses anchorage-independent proliferation and tumor growth in vivo. K254 is also a minor SUMOylation site.\",\n      \"method\": \"In vivo and in vitro SUMOylation assays; site-directed mutagenesis (K266R, K254R); membrane fractionation; AKT phosphorylation assay; soft-agar and xenograft tumor assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis, membrane fractionation, and in vivo tumor suppression assay; multiple orthogonal methods; mechanistic basis (electrostatic membrane binding) established\",\n      \"pmids\": [\"22713753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SUMO-1 occupies chromatin at promoters of actively transcribed housekeeping genes (including translation factors and ribosomal subunit genes) from G1 through late S phase but not mitosis, correlating with H3K4me3 marks. Depletion of SUMO-1 downregulates these SUMO-1-marked genes, indicating that chromatin-associated SUMO-1 positively marks and activates transcription of ribosome biogenesis and translation genes.\",\n      \"method\": \"ChIP-seq (SUMO-1 chromatin occupancy across cell cycle); SUMO-1 siRNA depletion; gene expression analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus depletion functional consequence; single lab, genome-scale but targeted functional validation\",\n      \"pmids\": [\"22941651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CDK6 is SUMOylated by SUMO1 at K216, which blocks ubiquitination at K147, stabilizing CDK6 protein throughout the cell cycle. CDK1 phosphorylates Ubc9, which in turn mediates CDK6 SUMOylation during mitosis; CDK6 remains SUMOylated in G1 to drive G1/S transition. This SUMOylation-stabilization mechanism promotes glioblastoma progression.\",\n      \"method\": \"In vivo and in vitro SUMOylation/ubiquitination assays; site-directed mutagenesis (K216R, K147R); cell cycle synchronization; Ubc9 phosphorylation by CDK1 in vitro; CDK6 stability assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase and SUMOylation assays, mutagenesis, and cell cycle-resolved mechanism; multiple orthogonal methods\",\n      \"pmids\": [\"24953629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Akt directly phosphorylates SUMO1 at T76, stabilizing the SUMO1 protein, and phosphorylates Ubc9 at T35, promoting Ubc9 thioester bond formation. These modifications by Akt enhance global SUMOylation and alter substrate SUMOylation specificity (STAT1, CREB), creating a mechanism by which Akt SUMOylation regulates cell proliferation through cyclin D1.\",\n      \"method\": \"In vitro kinase assays (Akt phosphorylating Ubc9 and SUMO1); site-directed mutagenesis (T35, T76); thioester bond formation assay; global SUMOylation assessment; cyclin D1/cell proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis and functional readouts; single lab, multiple methods\",\n      \"pmids\": [\"25867063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The RanBP2/RanGAP1*SUMO1/Ubc9 complex at the nuclear pore functions as an autonomous disassembly machine for Crm1-dependent nuclear export complexes, with preference for Crm1 over other exportins. Three in vitro reconstituted disassembly intermediates were characterized: Crm1 export complex binding via FG-repeat patches, cargo release by RanBP2's Ran-binding domains, and Crm1 retention after Ran-GTP hydrolysis. All intermediates are compatible with SUMO E3 ligase activity.\",\n      \"method\": \"In vitro reconstitution of disassembly intermediates with purified components; biochemical characterization of intermediates; E3 ligase activity assay in the context of export complex disassembly\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — fully reconstituted in vitro disassembly machine; multiple intermediates biochemically defined; mechanistic coupling of export and SUMOylation demonstrated\",\n      \"pmids\": [\"27160050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PKD2 (polycystin-2) channels in arterial smooth muscle myocytes undergo triple SUMO1 modification; SUMO-PKD2 cycles between the plasma membrane and intracellular compartments. Intravascular pressure activates voltage-dependent Ca2+ influx, which promotes return of internalized SUMO-PKD2 to the plasma membrane. Reduced pressure, hyperpolarization, or Ca2+ influx inhibition causes lysosomal degradation of internalized SUMO-PKD2, reducing surface channel density. Desumoylation leads to loss of Na+ current activation and vasodilation.\",\n      \"method\": \"Inducible cell-specific Pkd2 knockout mice; biochemical SUMOylation assay; patch-clamp electrophysiology; live-cell trafficking assay; lysosomal inhibition; Ca2+ channel blockade\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-specific KO, electrophysiology, and trafficking assay; mechanistic pathway from pressure to SUMO-PKD2 surface density established with multiple orthogonal approaches\",\n      \"pmids\": [\"31822608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NLRP3 is SUMOylated by SUMO1 at K204 (mediated by Ubc9), which facilitates ASC oligomerization and NLRP3 inflammasome activation and IL-1β secretion. SENP3 deSUMOylates NLRP3 at this site to attenuate ASC recruitment, inflammasome activation, and IL-1β cleavage.\",\n      \"method\": \"In vivo and in vitro SUMOylation assays; site-directed mutagenesis (K204R); co-immunoprecipitation (Ubc9–NLRP3); ASC oligomerization assay; IL-1β secretion assay; SENP3 overexpression/knockdown\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis, E2 interaction, functional ASC/IL-1β readouts; single lab\",\n      \"pmids\": [\"31914638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SUMO1 modification of KHSRP at K87 (enhanced by hypoxia) inhibits its interaction with the pri-miRNA/Drosha-DGCR8 complex and promotes KHSRP translocation from nucleus to cytoplasm. This impairs processing of pre-miRNAs from pri-miRNAs that harbor short G-rich stretches in their terminal loops (TL-G-Rich miRNAs, including let-7 family), resulting in their downregulation and consequent tumorigenesis.\",\n      \"method\": \"In vivo and in vitro SUMOylation assays; site-directed mutagenesis (K87); nuclear/cytosol fractionation; co-immunoprecipitation with Drosha-DGCR8; RNA immunoprecipitation; high-throughput miRNA sequencing; xenograft tumor model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis, fractionation, RNA-IP, and in vivo tumor model; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29020972\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SUMO1 functions as a post-translational modifier that is activated by the E1 heterodimer (SAE1/SAE2/Sua1/hUba2), transferred to substrates via the sole E2 enzyme Ubc9, and often facilitated by E3 ligases (RanBP2, PIAS family), following cleavage of its C-terminal four residues to expose a diglycine motif that forms an isopeptide bond with lysine residues in a PsiKXE consensus; unlike ubiquitin, SUMO1 conjugation does not primarily target substrates for proteasomal degradation but instead regulates protein localization (directing RanGAP1 to nuclear pores/kinetochores, PML to nuclear bodies, PTEN to the plasma membrane), protein–protein interactions, transcriptional activity (repressing Sp3, c-Jun, HDAC1; activating p53, HSF1, GATA4), and protein stability (protecting IκBα, Smad4, phosducin, and CDK6 from ubiquitin-dependent degradation), with the modification reversible via SENP-family isopeptidases and crosstalk with phosphorylation and ubiquitination determining the net regulatory outcome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SUMO1 is a small ubiquitin-like protein that is covalently and reversibly conjugated to lysine residues of target proteins, operating through a minimal enzymatic cascade and broadly reprogramming protein localization, stability, and transcriptional activity rather than marking substrates for degradation [#3, #5]. Conjugation requires only two upstream steps relative to ubiquitin: the Sua1p/hUba2 E1 heterodimer forms a SUMO1 thioester and the sole E2 enzyme Ubc9 transfers SUMO1 to substrate lysines within a transferable PsiKXE consensus motif, with in vivo modification additionally requiring nuclear targeting [#3, #5]. A defining functional theme is the control of subcellular localization: SUMO1 modification of RanGAP1 docks it onto the nucleoporin RanBP2/Nup358 at the nuclear pore and, during mitosis, at kinetochores and spindles [#1, #20], directs PTEN to the plasma membrane via electrostatic C2-domain contacts [#34], and is required for PML to nucleate PML nuclear bodies that recruit Sp100, CBP, Daxx and other components [#8]. SUMO1 also acts as a transcriptional rheostat—repressing Sp3, c-Jun, and HDAC1 while activating p53, HSF1, and GATA4—and is itself integrated with phosphorylation, since modification of c-Jun and p53 is antagonized by site-specific kinase activity [#11, #16, #4, #15, #23]. A second major theme is protein stabilization through competition with ubiquitin: SUMO1 conjugation at lysines that overlap or block ubiquitination protects IkBalpha, Smad4, phosducin, and CDK6 from proteasomal turnover [#0, #21, #28, #36]. The RanBP2/RanGAP1-SUMO1/Ubc9 assembly at the pore is itself a SUMO1-specific E3 ligase and an autonomous disassembly machine for Crm1-dependent nuclear export complexes, structurally explaining SUMO1 paralogue preference [#33, #38]. Reversal is achieved by SENP-family isopeptidases, whose pore association (SENP2-Nup153) or expression level shapes the cellular spectrum of SUMO1 conjugates [#18, #17, #30]. Gene-targeted Sumo1-null mice are viable and fertile, indicating that most SUMO1 functions are compensated at the protein level by SUMO2/3 in vivo [#32].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that SUMO1 is a bona fide covalent protein modifier in cells answered whether it acts like ubiquitin and linked it to nuclear retention of substrates.\",\n      \"evidence\": \"Immunoblotting, fractionation, and immunofluorescence of PML and Sp100 in cells\",\n      \"pmids\": [\"9412458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conjugation seen only in vivo, not in vitro at this stage\", \"Acceptor lysines and enzymology unresolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of RanGAP1 modification and Ubc9 as a SUMO1-specific E2 defined the conjugation machinery and the prototype localization function—docking onto RanBP2 at nuclear pores.\",\n      \"evidence\": \"MS, K526R mutagenesis, in vitro import assays, E2 specificity assay, and co-IP\",\n      \"pmids\": [\"9442102\", \"9456312\", \"9427648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E1 components not yet defined\", \"How modification creates the RanBP2 binding site not structurally resolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstration that SUMO1 conjugates IkBalpha at the same lysine used by ubiquitin established the antagonistic, stabilizing (non-degradative) logic of SUMOylation.\",\n      \"evidence\": \"In vitro SUMOylation with E1/Ubc9, K21 mutagenesis, NF-kB reporter assays\",\n      \"pmids\": [\"9734360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase and in vivo stoichiometry not addressed\", \"Generality of lysine competition unknown at the time\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Reconstitution with the Sua1p/hUba2 E1 heterodimer plus Ubc9 showed SUMO1 needs only a two-step cascade, distinguishing it mechanistically from ubiquitin.\",\n      \"evidence\": \"In vitro reconstitution with recombinant E1/E2 and thioester assay\",\n      \"pmids\": [\"9920803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role and necessity of E3 ligases not yet defined\", \"Substrate selection determinants unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Single-site modification of p53 at K386 that activates transcription, plus PML modification at its NLS via Ubc9-RING binding, generalized SUMO1 beyond localization to direct transcriptional and substrate-fate control.\",\n      \"evidence\": \"In vitro/in vivo SUMOylation, mutagenesis (K386R), transactivation reporters, yeast two-hybrid\",\n      \"pmids\": [\"10562557\", \"10562558\", \"9885291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SUMO1 alters p53 transactivation not defined\", \"Whether degradation effect on PML-RARalpha holds in vivo\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Definition of the transferable PsiKXE consensus (with a nuclear-targeting requirement in vivo) provided the predictive rule for SUMO1 substrate recognition.\",\n      \"evidence\": \"Peptide-transfer in vitro/in vivo assays, mutagenesis, NLS manipulation\",\n      \"pmids\": [\"11124955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Non-consensus sites not explained\", \"How nuclear targeting couples to conjugation efficiency unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Multiple substrates revealed SUMO1 as a transcriptional rheostat and stability switch integrated with phosphorylation—negatively regulating c-Jun and AR, modulating Mdm2/p53, and being antagonized by site-specific kinases.\",\n      \"evidence\": \"In vitro/in vivo SUMOylation, mutagenesis, transactivation and apoptosis assays, JNK activation\",\n      \"pmids\": [\"10788439\", \"11121022\", \"10892746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligases for these substrates not yet identified\", \"Quantitative crosstalk between SUMO and phospho-marks not modeled\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"PML-null complementation showed SUMO1 conjugation of PML is a prerequisite for PML nuclear body assembly, establishing SUMO1 as an organizer of a subnuclear compartment.\",\n      \"evidence\": \"PML-/- primary cells re-expressing WT vs SUMO-deficient PML; immunofluorescence of multiple NB markers\",\n      \"pmids\": [\"10779416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SUMO1 acts via covalent conjugation alone or also SIM-mediated assembly not separated\", \"Order of recruitment of NB components unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"SUMO1-versus-SUMO2/3 paralogue-specific substrate preferences and stress-induced SUMO2/3 conjugation distinguished paralogue functions, while TOP1/TOPII modification linked SUMO1 to genotoxic and conformational stress responses.\",\n      \"evidence\": \"Paralogue-specific antibodies, heat-shock, co-IP, ubc9 yeast epistasis with camptothecin\",\n      \"pmids\": [\"10692421\", \"10759568\", \"10862613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acceptor lysines on topoisomerases not mapped\", \"Functional consequence for DNA repair beyond CPT sensitivity unclear\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showing SUMO1 converts HSF1 to its DNA-binding form connected SUMO1 directly to activation of a stress-responsive transcription factor and to nuclear stress granules.\",\n      \"evidence\": \"Reconstituted in vitro SUMOylation, supershift EMSA, K298R mutagenesis, colocalization\",\n      \"pmids\": [\"11514557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stress signal that triggers HSF1 SUMOylation not defined\", \"E3 ligase unidentified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mitotic targeting of RanGAP1 to kinetochores/spindles and the SuPr-1/SENP2 deconjugation studies established the dynamic, reversible nature of SUMO1 modification and its spatial confinement at the pore.\",\n      \"evidence\": \"SUMO-deficient RanGAP1 mutant imaging, SUMO protease activity assays, SENP2-Nup153 co-IP, PML-null epistasis\",\n      \"pmids\": [\"11854305\", \"12419228\", \"11896061\", \"12419227\", \"11960997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate selectivity rules for individual SENPs incomplete\", \"How deconjugation timing is regulated during cell cycle unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Gain/loss-of-function on Smad4 demonstrated that SUMO1 stabilizes substrates by protecting them from ubiquitin-dependent degradation, generalizing the IkBalpha paradigm.\",\n      \"evidence\": \"Ubc9/SUMO1 overexpression and siRNA, fractionation, half-life and ubiquitination assays, TGF-beta reporter\",\n      \"pmids\": [\"12813045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct acceptor lysine and E3 for Smad4 not pinned down here\", \"Whether localization vs stability dominates the phenotype unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"DRP1 modification placed SUMO1 at mitochondrial fission sites, extending its action to outer-membrane protein dynamics and organelle morphology.\",\n      \"evidence\": \"Co-IP, live YFP:SUMO1 imaging at fission sites, fractionation, DRP1 stability assay\",\n      \"pmids\": [\"14972687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DRP1 acceptor lysine not defined\", \"E3 ligase and physiological trigger unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The TDG-SUMO1 crystal structure provided atomic-level proof that SUMO1 can act allosterically—remodeling a substrate surface to drive DNA release—and that non-covalent SUMO contacts contribute to function.\",\n      \"evidence\": \"2.1 A X-ray structure plus interface mutagenesis and DNA-binding/release assays; XPC modification in NER-deficient lines\",\n      \"pmids\": [\"15959518\", \"16030353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of allosteric remodeling to other substrates untested\", \"In vivo turnover dynamics of TDG-SUMO1 not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defining the SIM as a beta-strand whose flanking acidic/phospho residues confer paralogue specificity explained how SUMO1 builds non-covalent interaction networks, and individual substrates (DJ-1, phosducin, SOD1) tied SUMO1 to stability and disease.\",\n      \"evidence\": \"Yeast two-hybrid, NMR mapping; substrate mutagenesis and stability/aggregation assays\",\n      \"pmids\": [\"16524884\", \"15976810\", \"16421094\", \"16828461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative affinity rules for SIM-SUMO1 binding incomplete\", \"Disease-relevance (DJ-1 L166P, SOD1) shown largely in overexpression systems\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linking SUMO1-PML and SENP1 to DAXX recruitment and Fas-resistance in RA synovial fibroblasts connected the SUMO1 cycle to a disease-relevant apoptotic phenotype.\",\n      \"evidence\": \"Overexpression/knockdown, IP, DAXX-PML NB localization, Fas apoptosis assay, SENP1 rescue\",\n      \"pmids\": [\"17360386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality in primary disease tissue not fully established\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Phosphorylation of SUMO1's own N-terminal Ser2 and the viable Sumo1-null mouse established that the modifier itself is regulated and that SUMO2/3 compensate for most SUMO1 functions in vivo at the protein level.\",\n      \"evidence\": \"Endogenous MS across three species; Sumo1 knockout with RanGAP1 conjugation readout and phenotyping\",\n      \"pmids\": [\"18707152\", \"18573887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of SUMO1 Ser2 phosphorylation unknown\", \"Mechanism of SUMO2/3 compensation at substrate level not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Crystallographic and biochemical dissection of the RanBP2/RanGAP1-SUMO1/Ubc9 complex established it as a SUMO1-specific E3 ligase and explained paralogue preference at atomic resolution.\",\n      \"evidence\": \"Domain swaps, protease-protection, automodification, X-ray structures of UBC9-RanGAP1-SUMO1/2\",\n      \"pmids\": [\"22194619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How substrate diversity is achieved by a pore-anchored ligase unclear\", \"Regulation of this E3 in cells not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"PTEN K266 membrane targeting and SUMO1 chromatin occupancy at housekeeping/ribosome-biogenesis promoters expanded SUMO1's roles to PI3K/AKT tumor suppression and direct transcriptional activation of growth genes.\",\n      \"evidence\": \"SUMOylation/mutagenesis, membrane fractionation, AKT and xenograft assays; ChIP-seq with SUMO1 depletion\",\n      \"pmids\": [\"22713753\", \"22941651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How chromatin-bound SUMO1 mechanistically activates transcription unclear\", \"Whether PTEN membrane effect is conserved across tissues untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"CDK6 K216 SUMOylation blocking K147 ubiquitination, controlled by CDK1-phosphorylated Ubc9, integrated SUMO1-mediated stabilization into cell-cycle progression and glioblastoma.\",\n      \"evidence\": \"SUMOylation/ubiquitination assays, mutagenesis, cell-cycle synchronization, in vitro CDK1 kinase assay\",\n      \"pmids\": [\"24953629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase for CDK6 not identified\", \"In vivo tumor dependency not fully established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Reconstitution of the RanBP2 complex as an autonomous Crm1 export-complex disassembly machine coupled nuclear export termination to SUMO1 E3 activity at the pore.\",\n      \"evidence\": \"In vitro reconstitution of disassembly intermediates with purified components plus E3 activity assay\",\n      \"pmids\": [\"27160050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell coordination of disassembly and SUMOylation not demonstrated\", \"Selectivity for Crm1 over other exportins mechanism partial\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"PKD2 trafficking and NLRP3 inflammasome control demonstrated that reversible SUMO1 modification governs ion-channel surface density and innate immune signaling, with cognate SENPs reversing the effect.\",\n      \"evidence\": \"Cell-specific Pkd2 KO, patch-clamp, trafficking assays; NLRP3 mutagenesis, ASC oligomerization, IL-1beta, SENP3 modulation\",\n      \"pmids\": [\"31822608\", \"31914638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligases for PKD2 and NLRP3 not identified\", \"Physiological signals coupling SUMO1 cycling to function only partly defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How upstream signaling kinases (e.g., Akt phosphorylating SUMO1/Ubc9) and the choice of E3 ligase combine to dictate substrate-specific SUMO1 conjugation across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying rule linking E3 ligase repertoire to substrate selection\", \"Physiological triggers for many substrate modifications undefined\", \"Mechanism of SUMO2/3 compensation at the substrate level unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0031386\", \"supporting_discovery_ids\": [0, 1, 4, 5, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 9, 21, 28, 36]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 11, 16, 19, 23, 35]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [33, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1, 18, 38]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 6, 8, 16, 35]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [34, 39]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [35]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 5, 0, 21, 28, 36]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 11, 16, 19, 23, 35]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 20, 34, 38, 39]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13, 14, 24, 25]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [20, 36]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 40]}\n    ],\n    \"complexes\": [\n      \"RanBP2/RanGAP1-SUMO1/Ubc9 E3 ligase complex\",\n      \"PML nuclear bodies\"\n    ],\n    \"partners\": [\n      \"UBC9\",\n      \"SAE2\",\n      \"SAE1\",\n      \"RANBP2\",\n      \"RANGAP1\",\n      \"PIAS1\",\n      \"PML\",\n      \"SENP2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}