{"gene":"SENP6","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2000,"finding":"SUSP1 (SENP6) is a cysteine protease containing a conserved His/Asp/Cys catalytic triad that cleaves SUMO-1 from precursor fusion proteins (SUMO-1·β-galactosidase) in E. coli, demonstrating SUMO-1-specific maturation activity; GFP-SUSP1 localizes exclusively to the cytoplasm of NIH3T3 and HeLa cells.","method":"In vitro cleavage assay in E. coli, confocal microscopy of GFP fusion","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — in vitro activity assay with direct substrate, single lab, single study; localization by live imaging","pmids":["10799485"],"is_preprint":false},{"year":2006,"finding":"SUSP1 (SENP6) localizes within the nucleoplasm (not cytoplasm as initially reported) and its depletion causes redistribution of EGFP-SUMO2/3 (but not SUMO1) into enlarged, more numerous PML bodies due to a deficit of SUMO2/3 deconjugation; SUSP1 shows strong paralog bias toward SUMO2/3 and preferentially acts on substrates bearing three or more SUMO2/3 moieties.","method":"siRNA depletion, EGFP-SUMO live imaging, vinyl sulfone inhibitor profiling, model substrate assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (imaging, biochemical inhibitor profiling, model substrates), single lab but rigorous","pmids":["17000875"],"is_preprint":false},{"year":2006,"finding":"SUSP1 (SENP6) co-localizes with RXRα in the nucleus, removes SUMO-1 from RXRα (but not from androgen receptor or PPARγ), and its overexpression increases RXRα transcriptional activity, while shRNA knockdown decreases it; the SUMO-1 acceptor site on RXRα is Lys-108 within the AF-1 domain.","method":"Co-localization by confocal microscopy, in vitro/in vivo SUMOylation assays, overexpression/shRNA knockdown with luciferase reporter","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional assays (OE and KD) plus substrate identification, single lab","pmids":["16912044"],"is_preprint":false},{"year":2008,"finding":"SENP6 and SENP7 preferentially cleave SUMO2/3 in deconjugation reactions, with highest rates on di-SUMO2, di-SUMO3, and poly-SUMO2/3 chains, but exhibit lower rates than SENP2 for processing pre-SUMO1, pre-SUMO2, or pre-SUMO3; structure-guided mutagenesis identifies elements unique to the SENP6/SENP7 subclass that are required for poly-SUMO chain deconjugation.","method":"Crystal structure of SENP7 catalytic domain (2.4 Å), biochemical deconjugation assays with defined substrates, structure-guided mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro biochemical assays plus mutagenesis, multiple orthogonal methods in one rigorous study","pmids":["18799455"],"is_preprint":false},{"year":2010,"finding":"SENP6 depletion causes loss of the CENP-H/I/K complex from inner kinetochores, leading to spindle assembly defects and metaphase chromosome congression failure; CENP-I is degraded by RNF4 (a SUMO-targeted ubiquitin ligase) upon SENP6 depletion, and SENP6 stabilizes CENP-I by antagonizing RNF4-mediated polysumoylation-dependent proteasomal degradation.","method":"siRNA depletion, kinetochore composition analysis by immunofluorescence, proteasome inhibitor rescue, epistasis with RNF4","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular and molecular phenotype, genetic epistasis with RNF4, multiple readouts","pmids":["20212317"],"is_preprint":false},{"year":2010,"finding":"SENP6 depletion causes accumulation of endogenous SUMO-2/3 and SUMO-1 conjugates and increased number/size of PML nuclear bodies; catalytic-cysteine mutation of SENP6 causes its accumulation in PML NBs; biochemical analysis shows SUMO-modified PML is a direct substrate of SENP6; SENP6 can cleave mixed SUMO-1/SUMO-2/3 chains in addition to SUMO2/3 polymers.","method":"siRNA depletion, catalytic mutant trapping, immunofluorescence, biochemical substrate assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — substrate trapping with catalytic mutant plus biochemical assay plus imaging, multiple orthogonal methods","pmids":["21148299"],"is_preprint":false},{"year":2011,"finding":"A unique Loop1 insertion in the catalytic domain of SENP6 (and SENP7) is essential for proteolytic activity and forms an extended interface with SUMO during cleavage; a region on the SUMO surface determines SUMO2/3 isoform specificity; double point mutations on the SUMO surface swap the isoform specificity of SENP6/SENP7 between SUMO1 and SUMO2/3.","method":"Structure-based mutagenesis, in vitro biochemical cleavage assays with isoform-specific substrates","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis combined with biochemical assays defining structural basis of specificity, single lab but multiple orthogonal approaches","pmids":["21878624"],"is_preprint":false},{"year":2013,"finding":"SENP6 catalyzes de-SUMOylation of NEMO (IKKγ) at Lys-277, reversing SUMO-2/3 conjugation that normally impairs CYLD deubiquitinase binding to NEMO; SENP6 depletion potentiates NF-κB-mediated proinflammatory gene induction and increases susceptibility to endotoxin-induced sepsis in mice.","method":"siRNA knockdown, Co-IP, site-directed mutagenesis of NEMO Lys-277, luciferase reporter for NF-κB, in vivo endotoxin model","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct substrate identification with site-directed mutagenesis, Co-IP, functional reporters, and in vivo validation","pmids":["23825957"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of a SENP2-Loop1 chimera in complex with SUMO2 (2.15 Å) reveals the structural interface exclusive to SENP6/7 via Loop1 insertion; insertion of Loop1 into SENP2 increases proteolytic activity on diSUMO2 and polySUMO2 substrates, confirming Loop1 as the platform mediating SUMO2/3 specificity.","method":"Crystal structure of chimeric SENP2-Loop1:SUMO2 complex, in vitro cleavage assays with diSUMO2 and polySUMO2","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus in vitro functional validation with chimeric protein, single lab","pmids":["24424631"],"is_preprint":false},{"year":2018,"finding":"SENP6 interacts with, desumoylates, and stabilizes TRIM28; SENP6 loss in osteochondroprogenitors activates p53 signaling and SASP, leading to premature skeletal aging; Trp53 loss partially rescues the skeletal and cellular phenotypes of Senp6 knockout mice, establishing a SENP6–TRIM28–p53 epistatic axis.","method":"Conditional knockout mice, Co-IP, genetic epistasis (Senp6/Trp53 double mutant), cellular senescence and apoptosis assays, transcriptomic profiling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout plus genetic epistasis plus direct biochemical substrate identification, multiple orthogonal methods","pmids":["29321472"],"is_preprint":false},{"year":2019,"finding":"SENP6 harbors an N-terminal multi-SIM domain that targets it to SUMO chains; proteomic profiling identifies a network of SENP6 substrates at centromeric/telomeric chromatin, including the cohesin complex; SENP6 is part of the hPSO4/PRP19 complex; SENP6 deficiency impairs chromatin association of ATRIP, compromising ATR-Chk1 activation in response to replicative stress.","method":"Proteomics/mass spectrometry, domain deletion analysis, Co-IP of hPSO4/PRP19 complex, Chk1 phosphorylation assays, chromatin fractionation after aphidicolin treatment","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteomics, Co-IP, functional chromatin fractionation, signaling assays), single lab","pmids":["31597105"],"is_preprint":false},{"year":2019,"finding":"SENP6 knockdown identifies over 180 substrates conjugated to SUMO polymers including the entire CCAN complex and DNA damage response factors; SENP6 deficiency impairs accumulation of CENP-T, CENP-W, and CENP-A at centromeres and causes G2/M accumulation and micronuclei formation; increased SUMO chains on CCAN subunits do not trigger ubiquitin-dependent proteasomal degradation, indicating proteolysis-independent poly-SUMO signaling.","method":"SILAC-based quantitative proteomics after SENP6 knockdown, immunofluorescence for centromere proteins, flow cytometry, proteasome inhibitor experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative proteomics plus functional imaging plus mechanistic proteasome experiments, multiple orthogonal methods","pmids":["31485003"],"is_preprint":false},{"year":2021,"finding":"SENP6 mediates deSUMOylation of Annexin-A1 (ANXA1), promoting its nuclear translocation; deSUMOylated ANXA1 undergoes TRPM7- and PKC-dependent phosphorylation, activates p53 transcriptional activity, increases Bid expression, and triggers caspase-3-dependent neuronal apoptosis; expression of a SENP6 catalytic mutant in neurons improves neurological function in a mouse ischemia model.","method":"Co-IP, Ni2+-NTA pulldown for SUMOylation, luciferase reporter for p53, LDH/TUNEL assays, MCAO mouse model with catalytic mutant overexpression","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct substrate identification by pulldown/Co-IP plus in vivo functional validation with catalytic mutant, single lab","pmids":["34158860"],"is_preprint":false},{"year":2022,"finding":"SENP6 loss triggers release of DNA repair and genome maintenance protein complexes from chromatin, impairing DNA repair in response to DNA damage and promoting genomic instability; SENP6-deficient cells are synthetically lethal with PARP inhibition.","method":"Transposon mutagenesis screen in B-cell lymphoma model, chromatin fractionation, PARP inhibitor synthetic lethality assay, analysis of human lymphoma deletions","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic screen plus chromatin fractionation plus pharmacological epistasis, single lab","pmids":["35022408"],"is_preprint":false},{"year":2022,"finding":"SENP6-mediated deSUMOylation of ANXA1 in microglia targets the IKK complex and selectively inhibits autophagic degradation of IKKα in an NBR1-dependent manner, thereby activating the NF-κB pathway and promoting proinflammatory cytokine expression after ischemic stroke.","method":"Co-IP, AAV-mediated microglial SENP6 knockdown in vivo, NF-κB pathway analysis, autophagy assays","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo AAV knockdown plus mechanistic pathway analysis, single lab","pmids":["35869493"],"is_preprint":false},{"year":2023,"finding":"SENP6 deconjugates SUMO2/3 polymers from a group of DNA damage response proteins (BRCA1-BARD1, 53BP1, BLM, ERCC1-XPF) under unstressed conditions; SENP6 depletion causes uncoordinated recruitment and persistence of SUMO2/3 at DNA damage sites and accumulation of DDR proteins in PML-independent nuclear bodies driven by multivalent SUMO-SIM interactions; co-depletion of RNF4 further increases SUMOylation of BRCA1, BARD1 and BLM, indicating SENP6 antagonizes RNF4 targeting.","method":"Quantitative proteomics, immunofluorescence at UVA laser/IR damage sites, RNF4 epistasis (co-depletion), nuclear body analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — proteomics plus live-cell imaging at damage sites plus genetic epistasis, multiple orthogonal methods, single lab","pmids":["37735495"],"is_preprint":false},{"year":2023,"finding":"SENP6 depletion causes substantially increased SUMO modification of lamin A/C, producing nuclear structural changes resembling laminopathies; proximity-induced SUMO modification (PISM) directly targeting lamin A/C for SUMO conjugation recapitulates the altered nuclear structure, establishing a causal link between lamin SUMOylation and nuclear morphology changes.","method":"Proteomic identification of substrates by apparent molecular weight shift, PISM (DARPin-SUMO E3 ligase fusion) for targeted lamin SUMOylation, nuclear morphology imaging","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — engineered substrate-specific SUMOylation tool plus proteomics plus imaging, establishes causality, single lab with multiple orthogonal methods","pmids":["37556322"],"is_preprint":false},{"year":2024,"finding":"SENP6 constitutively interacts with USP8 and inhibits USP8 SUMOylation; deSUMOylated USP8 dissociates from IFNAR2, allowing increased IFNAR2 ubiquitination and degradation, thereby attenuating IFN-I antiviral signaling.","method":"Co-IP for SENP6-USP8 interaction, SUMOylation assays, IFNAR2 ubiquitination and degradation assays, IFN-I signaling readouts","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional ubiquitination/degradation assays plus signaling readouts, single lab","pmids":["38906982"],"is_preprint":false},{"year":2024,"finding":"SENP6 binds to and mediates deSUMOylation of Nrf2; deSUMOylated Nrf2 undergoes enhanced ubiquitination-dependent degradation, reducing its transcriptional activity and exacerbating neuronal oxidative stress after ischemic stroke; blocking SENP6-Nrf2 interaction with a cell-permeable peptide (Tat-Nrf2) preserves Nrf2 SUMOylation and attenuates oxidative stress.","method":"Co-IP, SUMOylation assay, ubiquitination assay, luciferase reporter for Nrf2 activity, Tat-Nrf2 peptide in vivo, MCAO mouse model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct substrate binding and deSUMOylation assays plus in vivo validation, single lab","pmids":["39716997"],"is_preprint":false},{"year":2025,"finding":"SENP6 knockdown-induced SUMOylation of TOM40 impairs TOM complex assembly, hindering mitochondrial protein import and disrupting mitochondrial morphology and function; in Alzheimer's disease contexts, Aβ1-42 decreases SENP6 in the mitochondrial fraction, increases TOM40 SUMOylation, and thereby impairs mitochondrial protein import.","method":"siRNA knockdown, TOM complex assembly assays, mitochondrial fractionation, mitochondrial import assays, 3×Tg-AD mouse model analysis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complex assembly and import assays plus in vivo model, single lab, single study","pmids":["40729740"],"is_preprint":false},{"year":2026,"finding":"SENP6 interacts with NLRP3 and deSUMOylates it at Lys-23, Lys-204, and Lys-689; deSUMOylation enables K48-linked polyubiquitination of NLRP3 by the E3 ligase MARCHF7, targeting NLRP3 for autophagy-lysosomal degradation; SENP6-deficient macrophages show enhanced NLRP3 inflammasome activation and increased IL-1β/IL-18 secretion.","method":"Co-IP, site-directed mutagenesis of NLRP3 SUMOylation sites, ubiquitination assays, autophagy-lysosome pathway inhibitors, SENP6 KO macrophages, in vivo LPS and alum models","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-directed mutagenesis plus Co-IP plus functional degradation assays plus in vivo model, single lab","pmids":["41531891"],"is_preprint":false},{"year":2026,"finding":"SENP6 knockdown in periodontal ligament stem cells stabilizes SMAD5 protein and upregulates SOX2 and early osteogenic markers (ALP, RUNX2); mechanistically, SENP6 desumoylates SMAD5, promoting its degradation, and SMAD5 directly activates SOX2 transcription; pharmacological SENP6 inhibition promotes bone formation in an LPS-induced calvarial osteolysis mouse model.","method":"siRNA knockdown, Co-IP, luciferase reporter assay for SOX2 promoter, in vivo mouse calvarial model with SENP6 inhibitor NSC632839","journal":"European journal of medical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct substrate Co-IP plus luciferase reporter plus in vivo pharmacological validation, single lab","pmids":["41618460"],"is_preprint":false},{"year":2023,"finding":"SENP6 deSUMOylates VEGFR2, and this deSUMOylation reduces VEGFR2 accumulation in the Golgi and promotes its transport to the cell membrane surface via coatomer protein complex subunit beta 2, enhancing VEGF signaling and pathological angiogenesis.","method":"Immunoblotting, immunofluorescence for subcellular VEGFR2 localization, SENP6 overexpression/knockdown in HUVECs","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, immunofluorescence and immunoblotting without direct biochemical deSUMOylation assay described in abstract","pmids":["36768878"],"is_preprint":false},{"year":2024,"finding":"SENP6 interacts with PINK1, reduces SUMO2ylation of PINK1, and thereby enhances mitophagy, promoting temozolomide resistance in glioblastoma cells.","method":"Co-IP for SENP6-PINK1 interaction, SUMO2 modification assay, mitophagy assays, temozolomide resistance assays","journal":"Molekuliarnaia biologiia","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus functional mitophagy assay, single lab, limited mechanistic detail in abstract","pmids":["38062972"],"is_preprint":false}],"current_model":"SENP6 (SUSP1/KIAA0797) is a nucleoplasmic SUMO isopeptidase with a His/Asp/Cys catalytic triad and an N-terminal multi-SIM targeting domain that preferentially disassembles poly-SUMO2/3 chains from substrates; its Loop1 insertion mediates SUMO2/3 isoform specificity; it acts as a global regulator of chromatin-associated SUMO dynamics, maintaining inner kinetochore integrity (CENP-H/I/K complex stability by antagonizing RNF4-dependent degradation), centromeric/telomeric chromatin organization (cohesin, CCAN), DNA damage response protein localization (BRCA1-BARD1, 53BP1, BLM), ATR-Chk1 signaling through the hPSO4/PRP19 complex, nuclear lamina integrity (lamin A/C), and NF-κB signaling (via NEMO deSUMOylation), as well as mitochondrial protein import (via TOM40 deSUMOylation) and transcriptional regulation of specific factors (RXRα, Nrf2, SMAD5, TRIM28/p53)."},"narrative":{"mechanistic_narrative":"SENP6 (SUSP1/KIAA0797) is a nucleoplasmic SUMO isopeptidase that serves as a global regulator of chromatin-associated SUMO dynamics by preferentially disassembling poly-SUMO2/3 chains from substrates [PMID:17000875, PMID:31485003]. It is a cysteine protease built around a conserved His/Asp/Cys catalytic triad [PMID:10799485], and a Loop1 insertion unique to the SENP6/SENP7 subclass forms an extended interface with SUMO that both confers proteolytic activity and dictates SUMO2/3 isoform specificity, while an N-terminal multi-SIM domain targets the enzyme to SUMO chains [PMID:18799455, PMID:21878624, PMID:24424631, PMID:31597105]. SENP6 shows strong paralog bias toward SUMO2/3 and acts most efficiently on substrates carrying three or more SUMO moieties [PMID:17000875, PMID:18799455]. Functionally, it maintains inner kinetochore and centromeric integrity by antagonizing RNF4-dependent, polysumoylation-driven proteasomal degradation of CENP-H/I/K and the broader CCAN, with some CCAN poly-SUMO signaling being proteolysis-independent [PMID:20212317, PMID:31485003]. SENP6 also governs the DNA damage response, deconjugating SUMO2/3 from BRCA1-BARD1, 53BP1, BLM and ERCC1-XPF to coordinate their chromatin association, supporting ATR-Chk1 signaling through the hPSO4/PRP19 complex, and its loss drives genomic instability and synthetic lethality with PARP inhibition [PMID:31597105, PMID:35022408, PMID:37735495]. Beyond chromatin, SENP6 deSUMOylates discrete substrates to control nuclear lamina integrity (lamin A/C) [PMID:37556322], NF-κB and inflammasome signaling (NEMO, NLRP3) [PMID:23825957, PMID:41531891], transcription factor stability (TRIM28/p53, Nrf2, SMAD5, RXRα) [PMID:16912044, PMID:29321472, PMID:39716997, PMID:41618460], and mitochondrial protein import via TOM40 [PMID:40729740].","teleology":[{"year":2000,"claim":"Established that SENP6 is an enzyme — a cysteine protease with a defined catalytic triad capable of processing SUMO, defining the molecular activity that all later substrate work would build on.","evidence":"In vitro cleavage of SUMO-1·β-galactosidase in E. coli and GFP-fusion imaging","pmids":["10799485"],"confidence":"Medium","gaps":["Localization initially miscalled as cytoplasmic","SUMO paralog preference not yet defined","No physiological substrate identified"]},{"year":2006,"claim":"Resolved SENP6's true compartment and specificity, showing it is nucleoplasmic and acts on poly-SUMO2/3 conjugates, reframing it as a chain-editing enzyme rather than a SUMO1 maturase.","evidence":"siRNA depletion with EGFP-SUMO live imaging, vinyl sulfone inhibitor profiling, and model substrates; plus RXRα co-localization and deSUMOylation","pmids":["17000875","16912044"],"confidence":"High","gaps":["Endogenous chromatin substrates not yet mapped","Mechanism of SUMO2/3 chain preference structurally undefined"]},{"year":2011,"claim":"Defined the structural basis of SENP6/SENP7 poly-SUMO2/3 specificity, explaining how the subclass discriminates chain length and isoform — the mechanistic core of its enzymology.","evidence":"Crystal structures (SENP7 catalytic domain; SENP2-Loop1:SUMO2 chimera), structure-guided mutagenesis, and isoform-swap point mutants in biochemical cleavage assays","pmids":["18799455","21878624","24424631"],"confidence":"High","gaps":["Full-length SENP6 structure with multi-SIM domain not determined","How SIM-mediated targeting couples to catalysis unresolved"]},{"year":2010,"claim":"Connected SENP6 deSUMOylation to chromosome segregation, showing it preserves the inner kinetochore by counteracting RNF4-mediated SUMO-targeted degradation — the first cellular phenotype tied to its chain-editing activity.","evidence":"siRNA depletion, kinetochore composition by immunofluorescence, proteasome rescue, RNF4 epistasis; PML substrate trapping with catalytic mutant","pmids":["20212317","21148299"],"confidence":"High","gaps":["Scope of kinetochore substrates limited to CENP-H/I/K","Whether all substrates are RNF4 targets unknown"]},{"year":2013,"claim":"Extended SENP6 to immune signaling by identifying NEMO Lys-277 as a direct deSUMOylation site controlling NF-κB output, showing the enzyme regulates inflammation in vivo.","evidence":"siRNA knockdown, Co-IP, NEMO K277 mutagenesis, NF-κB reporter, and endotoxin sepsis mouse model","pmids":["23825957"],"confidence":"High","gaps":["Whether NEMO is poly- or mono-SUMOylated by this axis","Tissue specificity of the NF-κB effect"]},{"year":2019,"claim":"Mapped SENP6's substrate network at scale, establishing it as a global guardian of centromeric/telomeric chromatin and the DNA damage response, and showing poly-SUMO signaling can act independently of proteasomal degradation.","evidence":"SILAC quantitative proteomics after knockdown, domain-deletion of multi-SIM, hPSO4/PRP19 Co-IP, chromatin fractionation, Chk1 phosphorylation and centromere imaging","pmids":["31597105","31485003"],"confidence":"High","gaps":["Direct vs indirect substrates not all distinguished","Mechanism converting poly-SUMO into non-degradative signaling unclear"]},{"year":2018,"claim":"Demonstrated a physiological consequence of SENP6 loss in vivo through the TRIM28–p53 axis, linking deSUMOylation-dependent substrate stabilization to skeletal aging and senescence.","evidence":"Conditional knockout mice, Co-IP, Senp6/Trp53 double-mutant epistasis, senescence/SASP and transcriptomic profiling","pmids":["29321472"],"confidence":"High","gaps":["Direct SUMO acceptor sites on TRIM28 not pinpointed","Generalizability beyond osteochondroprogenitors"]},{"year":2023,"claim":"Refined SENP6's DDR and nuclear-architecture roles, showing it chain-edits specific repair factors under basal conditions and controls lamin A/C SUMOylation to set nuclear morphology, with causality established by engineered targeted SUMOylation.","evidence":"Quantitative proteomics, IR/UVA damage-site imaging, RNF4 co-depletion epistasis, and PISM (DARPin-SUMO E3) targeted lamin SUMOylation","pmids":["37735495","37556322"],"confidence":"High","gaps":["How multivalent SUMO-SIM body formation is normally restrained unclear","Lamin SUMO acceptor sites and laminopathy relevance to disease alleles not defined"]},{"year":2022,"claim":"Positioned SENP6 as a tumor-relevant genome-stability factor by showing its loss releases repair complexes from chromatin and creates a targetable PARP-inhibitor vulnerability.","evidence":"Transposon mutagenesis screen in B-cell lymphoma, chromatin fractionation, PARP inhibitor synthetic lethality, human lymphoma deletion analysis","pmids":["35022408"],"confidence":"Medium","gaps":["Which specific deSUMOylation events drive the PARPi vulnerability not isolated","Clinical applicability untested"]},{"year":2026,"claim":"Broadened the SENP6 substrate repertoire into disease-specific signaling — neuronal apoptosis, inflammasome activation, antiviral and oxidative-stress responses, osteogenesis, and mitochondrial import — each via deSUMOylation of a discrete substrate.","evidence":"Co-IP, site-directed mutagenesis, ubiquitination/degradation and reporter assays, and in vivo disease models (MCAO, LPS/alum, AD, calvarial osteolysis) for ANXA1, NLRP3, USP8, Nrf2, SMAD5, and TOM40","pmids":["34158860","35869493","38906982","39716997","40729740","41531891","41618460"],"confidence":"Medium","gaps":["Many substrates rest on single-lab Co-IP without reciprocal validation","Whether these are poly-SUMO2/3 or mono-SUMO substrates often unresolved","Direct vs indirect deSUMOylation not always biochemically reconstituted"]},{"year":null,"claim":"How SENP6 selects among its hundreds of poly-SUMO substrates in space and time — and how its multi-SIM targeting, chain-length preference, and RNF4 antagonism are coordinated across distinct compartments — remains unresolved.","evidence":"No single study integrates substrate selectivity with subcellular targeting","pmids":[],"confidence":"Medium","gaps":["No full-length structure linking multi-SIM to catalytic domain","Rules governing degradative vs non-degradative poly-SUMO signaling unknown","Regulation of SENP6 activity/localization by upstream signals uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,5,6,7,15]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,3,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,9,11,18]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1,5]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[10,11,13,15]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,16]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,11]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[10,13,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,20]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,9,18,20]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,9,18,21]}],"complexes":["hPSO4/PRP19 complex"],"partners":["RNF4","TRIM28","NEMO","USP8","NRF2","SMAD5","NLRP3","PINK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9GZR1","full_name":"Sentrin-specific protease 6","aliases":["SUMO-1-specific protease 1","Sentrin/SUMO-specific protease SENP6"],"length_aa":1112,"mass_kda":126.1,"function":"Protease that deconjugates SUMO1, SUMO2 and SUMO3 from targeted proteins. Processes preferentially poly-SUMO2 and poly-SUMO3 chains, but does not efficiently process SUMO1, SUMO2 and SUMO3 precursors. Deconjugates SUMO1 from RXRA, leading to transcriptional activation. Involved in chromosome alignment and spindle assembly, by regulating the kinetochore CENPH-CENPI-CENPK complex. Desumoylates PML and CENPI, protecting them from degradation by the ubiquitin ligase RNF4, which targets polysumoylated proteins for proteasomal degradation. Also desumoylates RPA1, thus preventing recruitment of RAD51 to the DNA damage foci to initiate DNA repair through homologous recombination","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9GZR1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SENP6","classification":"Common Essential","n_dependent_lines":1190,"n_total_lines":1208,"dependency_fraction":0.9850993377483444},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PRPF19","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SENP6","total_profiled":1310},"omim":[{"mim_id":"612846","title":"SENTRIN-SPECIFIC PROTEASE FAMILY, MEMBER 7; SENP7","url":"https://www.omim.org/entry/612846"},{"mim_id":"609758","title":"Na+/K+ TRANSPORTING ATPase-INTERACTING 2; NKAIN2","url":"https://www.omim.org/entry/609758"},{"mim_id":"605003","title":"SENTRIN-SPECIFIC PROTEASE FAMILY, MEMBER 6; SENP6","url":"https://www.omim.org/entry/605003"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SENP6"},"hgnc":{"alias_symbol":["SUSP1","KIAA0797"],"prev_symbol":[]},"alphafold":{"accession":"Q9GZR1","domains":[{"cath_id":"2.30.29","chopping":"443-531_541-601","consensus_level":"high","plddt":79.6498,"start":443,"end":601},{"cath_id":"3.30.310.130","chopping":"654-722_732-789_962-1094","consensus_level":"high","plddt":90.288,"start":654,"end":1094}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZR1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZR1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZR1-F1-predicted_aligned_error_v6.png","plddt_mean":54.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SENP6","jax_strain_url":"https://www.jax.org/strain/search?query=SENP6"},"sequence":{"accession":"Q9GZR1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9GZR1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9GZR1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZR1"}},"corpus_meta":[{"pmid":"17000875","id":"PMC_17000875","title":"SUSP1 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Induces Microglia Activation and Neuroinflammation through TLR4 Activation and SENP6 Modulation in the Adolescent Rat Hippocampus.","date":"2019","source":"Neural plasticity","url":"https://pubmed.ncbi.nlm.nih.gov/31781182","citation_count":41,"is_preprint":false},{"pmid":"29321472","id":"PMC_29321472","title":"Desumoylase SENP6 maintains osteochondroprogenitor homeostasis by suppressing the p53 pathway.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29321472","citation_count":32,"is_preprint":false},{"pmid":"21878624","id":"PMC_21878624","title":"Swapping small ubiquitin-like modifier (SUMO) isoform specificity of SUMO proteases SENP6 and SENP7.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21878624","citation_count":32,"is_preprint":false},{"pmid":"37735495","id":"PMC_37735495","title":"SENP6 regulates localization and nuclear condensation of DNA damage response proteins by group deSUMOylation.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37735495","citation_count":30,"is_preprint":false},{"pmid":"35022408","id":"PMC_35022408","title":"Genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35022408","citation_count":24,"is_preprint":false},{"pmid":"35869493","id":"PMC_35869493","title":"SENP6 induces microglial polarization and neuroinflammation through de-SUMOylation of Annexin-A1 after cerebral ischaemia-reperfusion injury.","date":"2022","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/35869493","citation_count":24,"is_preprint":false},{"pmid":"23461386","id":"PMC_23461386","title":"Inhibition of SENP6-induced radiosensitization of human hepatocellular carcinoma cells by blocking radiation-induced NF-κB 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(Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39716997","citation_count":10,"is_preprint":false},{"pmid":"36768878","id":"PMC_36768878","title":"SENP6-Mediated deSUMOylation of VEGFR2 Enhances Its Cell Membrane Transport in Angiogenesis.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36768878","citation_count":10,"is_preprint":false},{"pmid":"38906982","id":"PMC_38906982","title":"SENP6 restricts the IFN-I-induced signaling pathway and antiviral activity by deSUMOylating USP8.","date":"2024","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38906982","citation_count":7,"is_preprint":false},{"pmid":"37556322","id":"PMC_37556322","title":"SUMO protease SENP6 protects the nucleus from hyperSUMOylation-induced laminopathy-like alterations.","date":"2023","source":"Cell 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Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40729740","citation_count":2,"is_preprint":false},{"pmid":"41531891","id":"PMC_41531891","title":"SENP6 Restrains NLRP3 Inflammasome Activation via DeSUMOylation-Driven K48-Linked Ubiquitination of NLRP3 in Acute Lung Injury.","date":"2026","source":"Research (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/41531891","citation_count":1,"is_preprint":false},{"pmid":"41494663","id":"PMC_41494663","title":"Anisomycin Induces Senescence and Death of Ovarian Cancer Stem Cells Through the MicroRNA-340/SENP6/SUMOylation Pathway.","date":"2026","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41494663","citation_count":0,"is_preprint":false},{"pmid":"38062972","id":"PMC_38062972","title":"[Interaction of SENP6 with PINK1 Promotes Temozolomide Resistance in Neuroglioma Cells via Inducing the Mitophagy].","date":"2024","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/38062972","citation_count":0,"is_preprint":false},{"pmid":"41618460","id":"PMC_41618460","title":"SENP6-mediated desumoylation of SMAD5 regulates osteogenic fate in periodontal ligament stem cells.","date":"2026","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/41618460","citation_count":0,"is_preprint":false},{"pmid":"41963434","id":"PMC_41963434","title":"Association of single nucleotide polymorphisms in FILIP1-SENP6 and FTO with temporomandibular joint osteoarthritis: clinical and in silico study.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41963434","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16500,"output_tokens":6475,"usd":0.073313,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15176,"output_tokens":4258,"usd":0.091165,"stage2_stop_reason":"end_turn"},"total_usd":0.164478,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"SUSP1 (SENP6) is a cysteine protease containing a conserved His/Asp/Cys catalytic triad that cleaves SUMO-1 from precursor fusion proteins (SUMO-1·β-galactosidase) in E. coli, demonstrating SUMO-1-specific maturation activity; GFP-SUSP1 localizes exclusively to the cytoplasm of NIH3T3 and HeLa cells.\",\n      \"method\": \"In vitro cleavage assay in E. coli, confocal microscopy of GFP fusion\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — in vitro activity assay with direct substrate, single lab, single study; localization by live imaging\",\n      \"pmids\": [\"10799485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SUSP1 (SENP6) localizes within the nucleoplasm (not cytoplasm as initially reported) and its depletion causes redistribution of EGFP-SUMO2/3 (but not SUMO1) into enlarged, more numerous PML bodies due to a deficit of SUMO2/3 deconjugation; SUSP1 shows strong paralog bias toward SUMO2/3 and preferentially acts on substrates bearing three or more SUMO2/3 moieties.\",\n      \"method\": \"siRNA depletion, EGFP-SUMO live imaging, vinyl sulfone inhibitor profiling, model substrate assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (imaging, biochemical inhibitor profiling, model substrates), single lab but rigorous\",\n      \"pmids\": [\"17000875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SUSP1 (SENP6) co-localizes with RXRα in the nucleus, removes SUMO-1 from RXRα (but not from androgen receptor or PPARγ), and its overexpression increases RXRα transcriptional activity, while shRNA knockdown decreases it; the SUMO-1 acceptor site on RXRα is Lys-108 within the AF-1 domain.\",\n      \"method\": \"Co-localization by confocal microscopy, in vitro/in vivo SUMOylation assays, overexpression/shRNA knockdown with luciferase reporter\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional assays (OE and KD) plus substrate identification, single lab\",\n      \"pmids\": [\"16912044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SENP6 and SENP7 preferentially cleave SUMO2/3 in deconjugation reactions, with highest rates on di-SUMO2, di-SUMO3, and poly-SUMO2/3 chains, but exhibit lower rates than SENP2 for processing pre-SUMO1, pre-SUMO2, or pre-SUMO3; structure-guided mutagenesis identifies elements unique to the SENP6/SENP7 subclass that are required for poly-SUMO chain deconjugation.\",\n      \"method\": \"Crystal structure of SENP7 catalytic domain (2.4 Å), biochemical deconjugation assays with defined substrates, structure-guided mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro biochemical assays plus mutagenesis, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"18799455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SENP6 depletion causes loss of the CENP-H/I/K complex from inner kinetochores, leading to spindle assembly defects and metaphase chromosome congression failure; CENP-I is degraded by RNF4 (a SUMO-targeted ubiquitin ligase) upon SENP6 depletion, and SENP6 stabilizes CENP-I by antagonizing RNF4-mediated polysumoylation-dependent proteasomal degradation.\",\n      \"method\": \"siRNA depletion, kinetochore composition analysis by immunofluorescence, proteasome inhibitor rescue, epistasis with RNF4\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular and molecular phenotype, genetic epistasis with RNF4, multiple readouts\",\n      \"pmids\": [\"20212317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SENP6 depletion causes accumulation of endogenous SUMO-2/3 and SUMO-1 conjugates and increased number/size of PML nuclear bodies; catalytic-cysteine mutation of SENP6 causes its accumulation in PML NBs; biochemical analysis shows SUMO-modified PML is a direct substrate of SENP6; SENP6 can cleave mixed SUMO-1/SUMO-2/3 chains in addition to SUMO2/3 polymers.\",\n      \"method\": \"siRNA depletion, catalytic mutant trapping, immunofluorescence, biochemical substrate assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate trapping with catalytic mutant plus biochemical assay plus imaging, multiple orthogonal methods\",\n      \"pmids\": [\"21148299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A unique Loop1 insertion in the catalytic domain of SENP6 (and SENP7) is essential for proteolytic activity and forms an extended interface with SUMO during cleavage; a region on the SUMO surface determines SUMO2/3 isoform specificity; double point mutations on the SUMO surface swap the isoform specificity of SENP6/SENP7 between SUMO1 and SUMO2/3.\",\n      \"method\": \"Structure-based mutagenesis, in vitro biochemical cleavage assays with isoform-specific substrates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis combined with biochemical assays defining structural basis of specificity, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"21878624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SENP6 catalyzes de-SUMOylation of NEMO (IKKγ) at Lys-277, reversing SUMO-2/3 conjugation that normally impairs CYLD deubiquitinase binding to NEMO; SENP6 depletion potentiates NF-κB-mediated proinflammatory gene induction and increases susceptibility to endotoxin-induced sepsis in mice.\",\n      \"method\": \"siRNA knockdown, Co-IP, site-directed mutagenesis of NEMO Lys-277, luciferase reporter for NF-κB, in vivo endotoxin model\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct substrate identification with site-directed mutagenesis, Co-IP, functional reporters, and in vivo validation\",\n      \"pmids\": [\"23825957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of a SENP2-Loop1 chimera in complex with SUMO2 (2.15 Å) reveals the structural interface exclusive to SENP6/7 via Loop1 insertion; insertion of Loop1 into SENP2 increases proteolytic activity on diSUMO2 and polySUMO2 substrates, confirming Loop1 as the platform mediating SUMO2/3 specificity.\",\n      \"method\": \"Crystal structure of chimeric SENP2-Loop1:SUMO2 complex, in vitro cleavage assays with diSUMO2 and polySUMO2\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus in vitro functional validation with chimeric protein, single lab\",\n      \"pmids\": [\"24424631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SENP6 interacts with, desumoylates, and stabilizes TRIM28; SENP6 loss in osteochondroprogenitors activates p53 signaling and SASP, leading to premature skeletal aging; Trp53 loss partially rescues the skeletal and cellular phenotypes of Senp6 knockout mice, establishing a SENP6–TRIM28–p53 epistatic axis.\",\n      \"method\": \"Conditional knockout mice, Co-IP, genetic epistasis (Senp6/Trp53 double mutant), cellular senescence and apoptosis assays, transcriptomic profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout plus genetic epistasis plus direct biochemical substrate identification, multiple orthogonal methods\",\n      \"pmids\": [\"29321472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SENP6 harbors an N-terminal multi-SIM domain that targets it to SUMO chains; proteomic profiling identifies a network of SENP6 substrates at centromeric/telomeric chromatin, including the cohesin complex; SENP6 is part of the hPSO4/PRP19 complex; SENP6 deficiency impairs chromatin association of ATRIP, compromising ATR-Chk1 activation in response to replicative stress.\",\n      \"method\": \"Proteomics/mass spectrometry, domain deletion analysis, Co-IP of hPSO4/PRP19 complex, Chk1 phosphorylation assays, chromatin fractionation after aphidicolin treatment\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (proteomics, Co-IP, functional chromatin fractionation, signaling assays), single lab\",\n      \"pmids\": [\"31597105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SENP6 knockdown identifies over 180 substrates conjugated to SUMO polymers including the entire CCAN complex and DNA damage response factors; SENP6 deficiency impairs accumulation of CENP-T, CENP-W, and CENP-A at centromeres and causes G2/M accumulation and micronuclei formation; increased SUMO chains on CCAN subunits do not trigger ubiquitin-dependent proteasomal degradation, indicating proteolysis-independent poly-SUMO signaling.\",\n      \"method\": \"SILAC-based quantitative proteomics after SENP6 knockdown, immunofluorescence for centromere proteins, flow cytometry, proteasome inhibitor experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative proteomics plus functional imaging plus mechanistic proteasome experiments, multiple orthogonal methods\",\n      \"pmids\": [\"31485003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SENP6 mediates deSUMOylation of Annexin-A1 (ANXA1), promoting its nuclear translocation; deSUMOylated ANXA1 undergoes TRPM7- and PKC-dependent phosphorylation, activates p53 transcriptional activity, increases Bid expression, and triggers caspase-3-dependent neuronal apoptosis; expression of a SENP6 catalytic mutant in neurons improves neurological function in a mouse ischemia model.\",\n      \"method\": \"Co-IP, Ni2+-NTA pulldown for SUMOylation, luciferase reporter for p53, LDH/TUNEL assays, MCAO mouse model with catalytic mutant overexpression\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct substrate identification by pulldown/Co-IP plus in vivo functional validation with catalytic mutant, single lab\",\n      \"pmids\": [\"34158860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SENP6 loss triggers release of DNA repair and genome maintenance protein complexes from chromatin, impairing DNA repair in response to DNA damage and promoting genomic instability; SENP6-deficient cells are synthetically lethal with PARP inhibition.\",\n      \"method\": \"Transposon mutagenesis screen in B-cell lymphoma model, chromatin fractionation, PARP inhibitor synthetic lethality assay, analysis of human lymphoma deletions\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic screen plus chromatin fractionation plus pharmacological epistasis, single lab\",\n      \"pmids\": [\"35022408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SENP6-mediated deSUMOylation of ANXA1 in microglia targets the IKK complex and selectively inhibits autophagic degradation of IKKα in an NBR1-dependent manner, thereby activating the NF-κB pathway and promoting proinflammatory cytokine expression after ischemic stroke.\",\n      \"method\": \"Co-IP, AAV-mediated microglial SENP6 knockdown in vivo, NF-κB pathway analysis, autophagy assays\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo AAV knockdown plus mechanistic pathway analysis, single lab\",\n      \"pmids\": [\"35869493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SENP6 deconjugates SUMO2/3 polymers from a group of DNA damage response proteins (BRCA1-BARD1, 53BP1, BLM, ERCC1-XPF) under unstressed conditions; SENP6 depletion causes uncoordinated recruitment and persistence of SUMO2/3 at DNA damage sites and accumulation of DDR proteins in PML-independent nuclear bodies driven by multivalent SUMO-SIM interactions; co-depletion of RNF4 further increases SUMOylation of BRCA1, BARD1 and BLM, indicating SENP6 antagonizes RNF4 targeting.\",\n      \"method\": \"Quantitative proteomics, immunofluorescence at UVA laser/IR damage sites, RNF4 epistasis (co-depletion), nuclear body analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus live-cell imaging at damage sites plus genetic epistasis, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"37735495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SENP6 depletion causes substantially increased SUMO modification of lamin A/C, producing nuclear structural changes resembling laminopathies; proximity-induced SUMO modification (PISM) directly targeting lamin A/C for SUMO conjugation recapitulates the altered nuclear structure, establishing a causal link between lamin SUMOylation and nuclear morphology changes.\",\n      \"method\": \"Proteomic identification of substrates by apparent molecular weight shift, PISM (DARPin-SUMO E3 ligase fusion) for targeted lamin SUMOylation, nuclear morphology imaging\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — engineered substrate-specific SUMOylation tool plus proteomics plus imaging, establishes causality, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37556322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SENP6 constitutively interacts with USP8 and inhibits USP8 SUMOylation; deSUMOylated USP8 dissociates from IFNAR2, allowing increased IFNAR2 ubiquitination and degradation, thereby attenuating IFN-I antiviral signaling.\",\n      \"method\": \"Co-IP for SENP6-USP8 interaction, SUMOylation assays, IFNAR2 ubiquitination and degradation assays, IFN-I signaling readouts\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional ubiquitination/degradation assays plus signaling readouts, single lab\",\n      \"pmids\": [\"38906982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SENP6 binds to and mediates deSUMOylation of Nrf2; deSUMOylated Nrf2 undergoes enhanced ubiquitination-dependent degradation, reducing its transcriptional activity and exacerbating neuronal oxidative stress after ischemic stroke; blocking SENP6-Nrf2 interaction with a cell-permeable peptide (Tat-Nrf2) preserves Nrf2 SUMOylation and attenuates oxidative stress.\",\n      \"method\": \"Co-IP, SUMOylation assay, ubiquitination assay, luciferase reporter for Nrf2 activity, Tat-Nrf2 peptide in vivo, MCAO mouse model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct substrate binding and deSUMOylation assays plus in vivo validation, single lab\",\n      \"pmids\": [\"39716997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SENP6 knockdown-induced SUMOylation of TOM40 impairs TOM complex assembly, hindering mitochondrial protein import and disrupting mitochondrial morphology and function; in Alzheimer's disease contexts, Aβ1-42 decreases SENP6 in the mitochondrial fraction, increases TOM40 SUMOylation, and thereby impairs mitochondrial protein import.\",\n      \"method\": \"siRNA knockdown, TOM complex assembly assays, mitochondrial fractionation, mitochondrial import assays, 3×Tg-AD mouse model analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complex assembly and import assays plus in vivo model, single lab, single study\",\n      \"pmids\": [\"40729740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SENP6 interacts with NLRP3 and deSUMOylates it at Lys-23, Lys-204, and Lys-689; deSUMOylation enables K48-linked polyubiquitination of NLRP3 by the E3 ligase MARCHF7, targeting NLRP3 for autophagy-lysosomal degradation; SENP6-deficient macrophages show enhanced NLRP3 inflammasome activation and increased IL-1β/IL-18 secretion.\",\n      \"method\": \"Co-IP, site-directed mutagenesis of NLRP3 SUMOylation sites, ubiquitination assays, autophagy-lysosome pathway inhibitors, SENP6 KO macrophages, in vivo LPS and alum models\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-directed mutagenesis plus Co-IP plus functional degradation assays plus in vivo model, single lab\",\n      \"pmids\": [\"41531891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SENP6 knockdown in periodontal ligament stem cells stabilizes SMAD5 protein and upregulates SOX2 and early osteogenic markers (ALP, RUNX2); mechanistically, SENP6 desumoylates SMAD5, promoting its degradation, and SMAD5 directly activates SOX2 transcription; pharmacological SENP6 inhibition promotes bone formation in an LPS-induced calvarial osteolysis mouse model.\",\n      \"method\": \"siRNA knockdown, Co-IP, luciferase reporter assay for SOX2 promoter, in vivo mouse calvarial model with SENP6 inhibitor NSC632839\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct substrate Co-IP plus luciferase reporter plus in vivo pharmacological validation, single lab\",\n      \"pmids\": [\"41618460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SENP6 deSUMOylates VEGFR2, and this deSUMOylation reduces VEGFR2 accumulation in the Golgi and promotes its transport to the cell membrane surface via coatomer protein complex subunit beta 2, enhancing VEGF signaling and pathological angiogenesis.\",\n      \"method\": \"Immunoblotting, immunofluorescence for subcellular VEGFR2 localization, SENP6 overexpression/knockdown in HUVECs\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, immunofluorescence and immunoblotting without direct biochemical deSUMOylation assay described in abstract\",\n      \"pmids\": [\"36768878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SENP6 interacts with PINK1, reduces SUMO2ylation of PINK1, and thereby enhances mitophagy, promoting temozolomide resistance in glioblastoma cells.\",\n      \"method\": \"Co-IP for SENP6-PINK1 interaction, SUMO2 modification assay, mitophagy assays, temozolomide resistance assays\",\n      \"journal\": \"Molekuliarnaia biologiia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus functional mitophagy assay, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"38062972\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SENP6 (SUSP1/KIAA0797) is a nucleoplasmic SUMO isopeptidase with a His/Asp/Cys catalytic triad and an N-terminal multi-SIM targeting domain that preferentially disassembles poly-SUMO2/3 chains from substrates; its Loop1 insertion mediates SUMO2/3 isoform specificity; it acts as a global regulator of chromatin-associated SUMO dynamics, maintaining inner kinetochore integrity (CENP-H/I/K complex stability by antagonizing RNF4-dependent degradation), centromeric/telomeric chromatin organization (cohesin, CCAN), DNA damage response protein localization (BRCA1-BARD1, 53BP1, BLM), ATR-Chk1 signaling through the hPSO4/PRP19 complex, nuclear lamina integrity (lamin A/C), and NF-κB signaling (via NEMO deSUMOylation), as well as mitochondrial protein import (via TOM40 deSUMOylation) and transcriptional regulation of specific factors (RXRα, Nrf2, SMAD5, TRIM28/p53).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SENP6 (SUSP1/KIAA0797) is a nucleoplasmic SUMO isopeptidase that serves as a global regulator of chromatin-associated SUMO dynamics by preferentially disassembling poly-SUMO2/3 chains from substrates [#1, #11]. It is a cysteine protease built around a conserved His/Asp/Cys catalytic triad [#0], and a Loop1 insertion unique to the SENP6/SENP7 subclass forms an extended interface with SUMO that both confers proteolytic activity and dictates SUMO2/3 isoform specificity, while an N-terminal multi-SIM domain targets the enzyme to SUMO chains [#3, #6, #8, #10]. SENP6 shows strong paralog bias toward SUMO2/3 and acts most efficiently on substrates carrying three or more SUMO moieties [#1, #3]. Functionally, it maintains inner kinetochore and centromeric integrity by antagonizing RNF4-dependent, polysumoylation-driven proteasomal degradation of CENP-H/I/K and the broader CCAN, with some CCAN poly-SUMO signaling being proteolysis-independent [#4, #11]. SENP6 also governs the DNA damage response, deconjugating SUMO2/3 from BRCA1-BARD1, 53BP1, BLM and ERCC1-XPF to coordinate their chromatin association, supporting ATR-Chk1 signaling through the hPSO4/PRP19 complex, and its loss drives genomic instability and synthetic lethality with PARP inhibition [#10, #13, #15]. Beyond chromatin, SENP6 deSUMOylates discrete substrates to control nuclear lamina integrity (lamin A/C) [#16], NF-\\u03baB and inflammasome signaling (NEMO, NLRP3) [#7, #20], transcription factor stability (TRIM28/p53, Nrf2, SMAD5, RXR\\u03b1) [#2, #9, #18, #21], and mitochondrial protein import via TOM40 [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that SENP6 is an enzyme \\u2014 a cysteine protease with a defined catalytic triad capable of processing SUMO, defining the molecular activity that all later substrate work would build on.\",\n      \"evidence\": \"In vitro cleavage of SUMO-1\\u00b7\\u03b2-galactosidase in E. coli and GFP-fusion imaging\",\n      \"pmids\": [\"10799485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Localization initially miscalled as cytoplasmic\", \"SUMO paralog preference not yet defined\", \"No physiological substrate identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved SENP6's true compartment and specificity, showing it is nucleoplasmic and acts on poly-SUMO2/3 conjugates, reframing it as a chain-editing enzyme rather than a SUMO1 maturase.\",\n      \"evidence\": \"siRNA depletion with EGFP-SUMO live imaging, vinyl sulfone inhibitor profiling, and model substrates; plus RXR\\u03b1 co-localization and deSUMOylation\",\n      \"pmids\": [\"17000875\", \"16912044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous chromatin substrates not yet mapped\", \"Mechanism of SUMO2/3 chain preference structurally undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the structural basis of SENP6/SENP7 poly-SUMO2/3 specificity, explaining how the subclass discriminates chain length and isoform \\u2014 the mechanistic core of its enzymology.\",\n      \"evidence\": \"Crystal structures (SENP7 catalytic domain; SENP2-Loop1:SUMO2 chimera), structure-guided mutagenesis, and isoform-swap point mutants in biochemical cleavage assays\",\n      \"pmids\": [\"18799455\", \"21878624\", \"24424631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length SENP6 structure with multi-SIM domain not determined\", \"How SIM-mediated targeting couples to catalysis unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected SENP6 deSUMOylation to chromosome segregation, showing it preserves the inner kinetochore by counteracting RNF4-mediated SUMO-targeted degradation \\u2014 the first cellular phenotype tied to its chain-editing activity.\",\n      \"evidence\": \"siRNA depletion, kinetochore composition by immunofluorescence, proteasome rescue, RNF4 epistasis; PML substrate trapping with catalytic mutant\",\n      \"pmids\": [\"20212317\", \"21148299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Scope of kinetochore substrates limited to CENP-H/I/K\", \"Whether all substrates are RNF4 targets unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended SENP6 to immune signaling by identifying NEMO Lys-277 as a direct deSUMOylation site controlling NF-\\u03baB output, showing the enzyme regulates inflammation in vivo.\",\n      \"evidence\": \"siRNA knockdown, Co-IP, NEMO K277 mutagenesis, NF-\\u03baB reporter, and endotoxin sepsis mouse model\",\n      \"pmids\": [\"23825957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NEMO is poly- or mono-SUMOylated by this axis\", \"Tissue specificity of the NF-\\u03baB effect\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped SENP6's substrate network at scale, establishing it as a global guardian of centromeric/telomeric chromatin and the DNA damage response, and showing poly-SUMO signaling can act independently of proteasomal degradation.\",\n      \"evidence\": \"SILAC quantitative proteomics after knockdown, domain-deletion of multi-SIM, hPSO4/PRP19 Co-IP, chromatin fractionation, Chk1 phosphorylation and centromere imaging\",\n      \"pmids\": [\"31597105\", \"31485003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect substrates not all distinguished\", \"Mechanism converting poly-SUMO into non-degradative signaling unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a physiological consequence of SENP6 loss in vivo through the TRIM28\\u2013p53 axis, linking deSUMOylation-dependent substrate stabilization to skeletal aging and senescence.\",\n      \"evidence\": \"Conditional knockout mice, Co-IP, Senp6/Trp53 double-mutant epistasis, senescence/SASP and transcriptomic profiling\",\n      \"pmids\": [\"29321472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SUMO acceptor sites on TRIM28 not pinpointed\", \"Generalizability beyond osteochondroprogenitors\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Refined SENP6's DDR and nuclear-architecture roles, showing it chain-edits specific repair factors under basal conditions and controls lamin A/C SUMOylation to set nuclear morphology, with causality established by engineered targeted SUMOylation.\",\n      \"evidence\": \"Quantitative proteomics, IR/UVA damage-site imaging, RNF4 co-depletion epistasis, and PISM (DARPin-SUMO E3) targeted lamin SUMOylation\",\n      \"pmids\": [\"37735495\", \"37556322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How multivalent SUMO-SIM body formation is normally restrained unclear\", \"Lamin SUMO acceptor sites and laminopathy relevance to disease alleles not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioned SENP6 as a tumor-relevant genome-stability factor by showing its loss releases repair complexes from chromatin and creates a targetable PARP-inhibitor vulnerability.\",\n      \"evidence\": \"Transposon mutagenesis screen in B-cell lymphoma, chromatin fractionation, PARP inhibitor synthetic lethality, human lymphoma deletion analysis\",\n      \"pmids\": [\"35022408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which specific deSUMOylation events drive the PARPi vulnerability not isolated\", \"Clinical applicability untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Broadened the SENP6 substrate repertoire into disease-specific signaling \\u2014 neuronal apoptosis, inflammasome activation, antiviral and oxidative-stress responses, osteogenesis, and mitochondrial import \\u2014 each via deSUMOylation of a discrete substrate.\",\n      \"evidence\": \"Co-IP, site-directed mutagenesis, ubiquitination/degradation and reporter assays, and in vivo disease models (MCAO, LPS/alum, AD, calvarial osteolysis) for ANXA1, NLRP3, USP8, Nrf2, SMAD5, and TOM40\",\n      \"pmids\": [\"34158860\", \"35869493\", \"38906982\", \"39716997\", \"40729740\", \"41531891\", \"41618460\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many substrates rest on single-lab Co-IP without reciprocal validation\", \"Whether these are poly-SUMO2/3 or mono-SUMO substrates often unresolved\", \"Direct vs indirect deSUMOylation not always biochemically reconstituted\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SENP6 selects among its hundreds of poly-SUMO substrates in space and time \\u2014 and how its multi-SIM targeting, chain-length preference, and RNF4 antagonism are coordinated across distinct compartments \\u2014 remains unresolved.\",\n      \"evidence\": \"No single study integrates substrate selectivity with subcellular targeting\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full-length structure linking multi-SIM to catalytic domain\", \"Rules governing degradative vs non-degradative poly-SUMO signaling unknown\", \"Regulation of SENP6 activity/localization by upstream signals uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 5, 6, 7, 15]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 9, 11, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [10, 11, 13, 15]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 11]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [10, 13, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 20]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 9, 18, 20]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 9, 18, 21]}\n    ],\n    \"complexes\": [\"hPSO4/PRP19 complex\"],\n    \"partners\": [\"RNF4\", \"TRIM28\", \"NEMO\", \"USP8\", \"Nrf2\", \"SMAD5\", \"NLRP3\", \"PINK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}