{"gene":"UBE2V1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2005,"finding":"Uev1A (UBE2V1) and Mms2 differentially modulate the length of Ubc13-mediated Lys63-linked polyubiquitin chains; Ubc13-Uev1A is specifically required for NF-κB activation but not DNA damage repair, whereas Ubc13-Mms2 is required for DNA damage repair but not NF-κB activation, demonstrating that different Uev partners direct Ubc13 to distinct cellular processes through physical interaction.","method":"In vitro polyubiquitination assays, functional complementation, RNA interference knockdown, NF-κB reporter assays, DNA damage survival assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (in vitro chain-length assays, genetic complementation, RNAi knockdown, functional pathway assays), findings replicated across distinct cellular readouts","pmids":["16129784"],"is_preprint":false},{"year":2003,"finding":"TNF-induced activation of GCKR and the SAPK/JNK pathway requires the E2 complex Ubc13/Uev1A and the E3 TRAF2; TNF signaling leads to TRAF2 polyubiquitination and oligomerization and to GCKR ubiquitination and activation, all sensitive to disruption of Ubc13 function.","method":"Dominant-negative interference with Ubc13, siRNA knockdown of Ubc13, immunoprecipitation, kinase activity assays, co-immunoprecipitation of TRAF2 and GCKR","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, dominant-negative and RNAi approaches, kinase activity readouts, multiple orthogonal experiments in one study","pmids":["12591926"],"is_preprint":false},{"year":2007,"finding":"In an in vitro reconstituted system, UEV1A presents Lys63 of ubiquitin to suppress direct substrate modification while enabling Lys63-linked ubiquitin chain synthesis; protein modification with K63-linked chains occurs through a UEV1A-independent substrate modification step and a UEV1A-dependent chain-elongation mechanism.","method":"In vitro ubiquitination reconstitution assay with UBC13-UEV1A and TRAF6","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of enzymatic activity with defined components, mechanistic dissection of substrate vs. chain-building roles","pmids":["17709375"],"is_preprint":false},{"year":2006,"finding":"NMR structure of hUev1a determined; hUev1a interacts with ubiquitin and hUbc13; a structural model of the Ub-hUev1a-hUbc13-Ub tetramer proposes that a hydrogen-bond network involving hUbc13-Asp81 and Ub-Glu64 positions Ub-Lys63 proximal to the active site for K63-linked chain synthesis.","method":"NMR spectroscopy, structural modeling, restrained molecular dynamics simulations","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure determination with interaction mapping and MD simulations; single lab but multiple orthogonal biophysical methods","pmids":["16893187"],"is_preprint":false},{"year":1998,"finding":"UEV-1 (UBE2V1/CROC-1) proteins lack the catalytic cysteine of E2 enzymes and are catalytically inactive in vitro (cannot conjugate or transfer ubiquitin to substrates); constitutive expression of UEV in HT-29-M6 cells inhibited differentiation upon confluence, caused G2-M accumulation, and inhibited the mitotic kinase Cdk1.","method":"In vitro ubiquitin conjugation/transfer assay, sequence analysis, cell cycle analysis by flow cytometry, constitutive overexpression in HT-29-M6 cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro enzymatic assay establishing catalytic inactivity, plus gain-of-function cell biology with defined molecular (Cdk1) readout","pmids":["9418904"],"is_preprint":false},{"year":2012,"finding":"The small-molecule NSC697923 inhibits the Ubc13-Uev1A E2 complex by blocking formation of the Ubc13-ubiquitin thioester conjugate, thereby suppressing constitutive NF-κB activity and inhibiting proliferation and survival of DLBCL cells; Ubc13 knockdown similarly inhibited DLBCL cell survival.","method":"Small-molecule inhibitor screen, thioester conjugate formation assay, NF-κB reporter assay, siRNA knockdown, cell proliferation/survival assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — biochemical thioester assay, NF-κB reporter, and cell viability with both chemical inhibition and genetic knockdown, converging on same mechanism","pmids":["22791293"],"is_preprint":false},{"year":2018,"finding":"Ube2v1 promotes Ubc13-mediated ubiquitination and proteasomal degradation of Sirt1, leading to inhibition of histone H4 lysine 16 acetylation and epigenetic suppression of autophagy gene expression, which promotes EMT and metastasis in colorectal cancer.","method":"Quantitative mass spectrometry, immunoprecipitation, ubiquitination assay, Western blotting, immunofluorescence, in vivo xenograft model","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay plus co-IP and in vivo rescue, single lab with multiple orthogonal methods","pmids":["30016968"],"is_preprint":false},{"year":2014,"finding":"Uev1A-Ubc13 complex promotes breast cancer cell invasion and metastasis through NF-κB activation and upregulation of MMP1; this process requires functional Ubc13 (physical interaction with Uev1A is necessary), and depletion of UEV1 reduces MMP1 expression and prevents tumor formation/metastasis in xenograft mice.","method":"Overexpression and siRNA knockdown in MDA-MB-231 cells, NF-κB reporter assay, invasion/migration assays, xenograft mouse model, MMP1 rescue experiment","journal":"Breast cancer research : BCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic manipulation (OE and KD), NF-κB pathway readout, in vivo xenograft, and downstream effector rescue; single lab","pmids":["25022892"],"is_preprint":false},{"year":2017,"finding":"Uev1A-Ubc13 complex interacts with RHBDF2 and, upon TNFα stimulation cooperates with the E3 CHIP to promote K63-linked ubiquitination of RHBDF2, enhancing TACE maturation and subsequent shedding of the TNFα receptor to attenuate NF-κB signaling.","method":"Co-immunoprecipitation, K63-linked ubiquitination assay, TACE maturation assay, UEV1A overexpression and inhibition experiments","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, and functional TACE maturation readout; single lab, multiple methods","pmids":["29069608"],"is_preprint":false},{"year":2017,"finding":"Uev1A promotes osteosarcoma differentiation by collaborating with the E3 ligase Smurf1 to promote ubiquitination and degradation of Smad1 (a BMP signaling effector), and this process occurs in a Ubc13-independent manner.","method":"Co-immunoprecipitation, ubiquitination assay, Western blotting, UEV1A overexpression and knockdown, Smad1 as downstream effector readout","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay with Ubc13-independent mechanistic determination; single lab","pmids":["28771228"],"is_preprint":false},{"year":2020,"finding":"Ube2v1 positively regulates K63-linked ubiquitination to promote protein aggregate formation in cardiomyocytes; Ube2v1 knockdown improves ubiquitin proteasome system performance and promotes degradation of insoluble ubiquitinated proteins without altering autophagic flux; cardiomyocyte-specific Ube2v1 knockout alleviates CryABR120G-induced protein aggregation, improves cardiac function, and prolongs lifespan in vivo.","method":"Adenoviral overexpression/knockdown in neonatal rat ventricular cardiomyocytes, UPS reporter assay, AAV9-CRISPR cardiomyocyte-specific knockout in mice, echocardiography, autophagic flux assay","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo cardiac-specific KO with functional cardiac readout plus mechanistic UPS reporter assay, multiple orthogonal approaches","pmids":["32081062"],"is_preprint":false},{"year":2020,"finding":"The N-terminal extension of Uev1A (absent in Mms2) stimulates polyubiquitin chain assembly, weakens the Uev-Ubc13 interaction affinity, and is specifically required for NF-κB activation; a chimeric protein with the Uev1A N-terminus fused to Mms2 functionally resembles Uev1A, whereas truncated Uev1A lacking the N-terminal extension behaves like Mms2.","method":"In vitro polyubiquitination assay, thermodynamic binding measurements (ITC or equivalent), chimeric and truncation mutant functional assays, NF-κB reporter assay","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro enzymatic and thermodynamic assays combined with chimeric/truncation domain-swap analysis and cellular pathway readout; single lab but multiple orthogonal methods","pmids":["32659264"],"is_preprint":false},{"year":2006,"finding":"Constitutive high-level expression of UEV1A alone in human cells is sufficient to increase NF-κB activity, upregulate the anti-apoptotic protein Bcl-2, confer prolonged cell survival under serum deprivation, and protect against apoptosis from diverse stressing agents; all effects are reversible upon RNAi-mediated suppression of UEV1.","method":"Stable overexpression of UEV1A, NF-κB luciferase reporter assay, Western blotting, RNAi knockdown, cell survival/apoptosis assays","journal":"Apoptosis : an international journal on programmed cell death","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function and RNAi rescue, NF-κB pathway readout, and Bcl-2 as downstream effector; single lab","pmids":["17041755"],"is_preprint":false},{"year":2018,"finding":"Uev1A-Ubc13 promotes colorectal cancer metastasis through NF-κB activation and upregulation of CXCL1; UEV1A overexpression depends on its physical interaction with Ubc13 to promote invasion, and depletion of UEV1 reduces CXCL1 expression and prevents tumor growth in a xenograft model.","method":"Overexpression and siRNA knockdown in HCT116 cells, NF-κB reporter, invasion assay, xenograft mouse model, IHC of human samples","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — OE/KD with Ubc13-interaction dependency, NF-κB pathway and CXCL1 readout, in vivo xenograft; single lab","pmids":["29662619"],"is_preprint":false},{"year":2019,"finding":"UEV1A promotes breast cancer cell survival under serum starvation and chemoresistance through activation of the AKT signaling pathway that in turn inhibits FOXO1 and BIM expression; depletion of UEV1 inhibits AKT signaling and promotes FOXO1/BIM expression, reducing cell survival and enhancing chemosensitivity.","method":"Overexpression and siRNA knockdown of UEV1A in MDA-MB-231 and MCF7 cells, Western blotting for AKT/FOXO1/BIM, cell viability and chemosensitivity assays","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation with defined pathway readouts (AKT-FOXO1-BIM); single lab","pmids":["31827405"],"is_preprint":false},{"year":2010,"finding":"C. elegans UEV-1 (ortholog of UBE2V1) regulates trafficking of the AMPA-type glutamate receptor GLR-1; loss of uev-1 causes GLR-1 accumulation in RAB-10-containing endosomes in neuron cell bodies and along neurites, independent of clathrin-mediated endocytosis; ubc-13 mutants phenocopy uev-1 mutants, and UEV-1 can physically interact with C. elegans UBC-13.","method":"Forward genetic screen in C. elegans, fluorescence imaging of GLR-1::GFP, behavioral reversal assay, genetic epistasis with ubc-13, co-immunoprecipitation of UEV-1 and UBC-13, K63-ubiquitin immunostaining","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen, fluorescence localization, epistasis with ubc-13, and co-IP; single lab but multiple orthogonal methods in C. elegans ortholog","pmids":["21179194"],"is_preprint":false},{"year":2021,"finding":"UEV1A overexpression induces CT45A family gene expression in breast cancer cells and promotes cell migration and EMT signaling through the AKT pathway (independently of NF-κB); depletion of CT45A abolishes these effects, identifying CT45A as a critical downstream effector of Uev1A in AKT-dependent migration.","method":"UEV1A and CT45A overexpression/knockdown in breast cancer cells, gene expression profiling, cell migration assay, Western blotting for AKT and NF-κB pathway components","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation, pathway inhibitor analysis, and downstream effector rescue; single lab","pmids":["34503444"],"is_preprint":false},{"year":2020,"finding":"Drosophila Uev1a forms a stable heterodimer with Bendless (Drosophila Ubc13 ortholog); Uev1a-F15E mutation abolishes this interaction, and Uev1a-F15Y severely reduces it; dUev1a functionally rescues yeast mms2 null mutants in a Bendless-dependent manner, and heterozygous dUev1a mutant flies show increased sensitivity to DNA-damaging agents and reduced mobility consistent with neurological defects.","method":"Co-immunoprecipitation, site-directed mutagenesis (F15E, F15Y), yeast functional complementation, DNA damage sensitivity assay, Drosophila mutant behavioral analysis","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mutagenesis, cross-species complementation, and in vivo Drosophila phenotypic readouts; single lab","pmids":["32702441"],"is_preprint":false},{"year":2025,"finding":"UBE2V1 competes with HIF-1α for binding to the β-domain of VHL protein and, in complex with UBE2S, catalyzes K11/K48-linked ubiquitination of VHL at K196, leading to VHL proteasomal degradation, reduced HIF-1α ubiquitination, and sustained HIF-1α stabilization, creating a positive feedback loop in hepatocellular carcinoma.","method":"Co-immunoprecipitation, ubiquitination assay (K11/K48-specific), UBE2V1 overexpression/knockdown, HIF-1α reporter assay, VHL degradation assay, in vivo xenograft","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, site-specific ubiquitination assay with defined lysine (K196), and functional HIF-1α stabilization readout; single lab","pmids":["41446875"],"is_preprint":false},{"year":1998,"finding":"Human UEV-1A cDNA fully complements the UV and MMS sensitivity of a yeast YGL087c deletion mutant, demonstrating functional conservation of UEV proteins in DNA damage tolerance across species.","method":"Yeast deletion mutant complementation assay, DNA damage sensitivity assay (UV and MMS)","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cross-species functional complementation with defined genetic readout; single lab, single method","pmids":["9580084"],"is_preprint":false},{"year":1998,"finding":"Human UEV (CROC-1/hMMS2) genes complement yeast mms2 defects in DNA damage sensitivity and spontaneous mutagenesis, and both MMS2 and hMMS2 transactivate a c-fos-CAT reporter gene in mammalian cells, demonstrating functional conservation across species in both DNA repair and transcriptional activation.","method":"Yeast mms2 mutant complementation assay, transient co-transfection with c-fos-CAT reporter in Rat-1 cells","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cross-species genetic complementation and mammalian reporter assay; single lab, two independent functional readouts","pmids":["9705497"],"is_preprint":false},{"year":2025,"finding":"UBE2V1 positively regulates ubiquitinated protein aggregate formation in mouse oocytes; UBE2V1 expression increases with maternal aging and correlates with aggresome formation; restoring UBE2V1 expression in aged oocytes/embryos alleviates aggresome formation and partly ameliorates age-related defects in oocyte maturation and embryo development.","method":"Mouse model of advanced maternal age, UBE2V1 overexpression/knockdown in oocytes, immunofluorescence for ubiquitinated aggregates/aggresomes, oocyte maturation and embryo development assessment","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation with defined cellular readouts (aggresome formation, oocyte maturation); single lab","pmids":["40394227"],"is_preprint":false},{"year":2025,"finding":"Uev1A collaborates with the E3 APC/C complex to mediate proteasomal degradation of Cyclin A in Drosophila, representing a non-canonical (proteolytic) function; this protects polyploid nurse cells from oncogenic Ras-induced aberrant division stress; human UBE2V1 and UBE2V2 similarly counteract oncogenic Ras-driven tumorigenesis in vivo.","method":"Genome-wide genetic screen in Drosophila, genetic epistasis, Cyclin A degradation assay, xenograft tumor model in nude mice with human UBE2V1/UBE2V2 overexpression","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide screen, APC/C epistasis, Cyclin A degradation readout, and in vivo xenograft; published peer-reviewed, single study","pmids":["41879050"],"is_preprint":false}],"current_model":"UBE2V1 (Uev1A) is a catalytically inactive ubiquitin-conjugating enzyme variant that obligately heterodimerizes with Ubc13 to stimulate K63-linked polyubiquitin chain synthesis; the Uev1A–Ubc13 complex activates NF-κB (via TRAF2/TRAF6/NEMO ubiquitination), drives JNK/SAPK and AKT signaling, promotes K63-linked ubiquitination of substrates including RHBDF2 and Sirt1, and can also act in a Ubc13-independent manner (with Smurf1 to degrade Smad1 or with UBE2S/APC/C to degrade Cyclin A), with the unique N-terminal extension of Uev1A distinguishing its pro-NF-κB and polyubiquitin chain-assembly activity from the DNA-repair-directed Mms2–Ubc13 complex."},"narrative":{"mechanistic_narrative":"UBE2V1 (Uev1A/CROC-1) is a catalytically inactive ubiquitin-conjugating enzyme variant that lacks the canonical E2 active-site cysteine and cannot itself transfer ubiquitin, instead functioning as a specificity-determining cofactor that obligately heterodimerizes with the E2 Ubc13 to direct synthesis of Lys63-linked polyubiquitin chains [PMID:9418904, PMID:16129784]. Within this complex, Ubc13 catalyzes thioester-linked ubiquitin transfer while UBE2V1 binds and positions the acceptor ubiquitin so that its Lys63 lies proximal to the active site, enabling processive chain elongation distinct from the UBE2V1-independent initial substrate-modification step [PMID:17709375, PMID:16893187]. A unique N-terminal extension absent from the paralog Mms2 stimulates chain assembly, weakens the Uev-Ubc13 affinity, and specifically routes the complex toward NF-κB activation rather than DNA-damage tolerance, explaining why Ubc13-Uev1A drives inflammatory signaling while Ubc13-Mms2 serves DNA repair [PMID:32659264, PMID:16129784]. Functionally, Ubc13-Uev1A operates downstream of TNF through TRAF2 polyubiquitination to activate JNK/SAPK signaling [PMID:12591926] and is sufficient on its own to elevate NF-κB activity, upregulate Bcl-2, and confer apoptotic resistance [PMID:17041755]; this activity is pharmacologically tractable, as the inhibitor NSC697923 blocks Ubc13~ubiquitin thioester formation and suppresses NF-κB-dependent lymphoma survival [PMID:22791293]. Through NF-κB- and AKT-driven programs, UBE2V1 promotes cancer cell invasion, metastasis, and chemoresistance via effectors including MMP1, CXCL1, and AKT-FOXO1-BIM signaling [PMID:25022892, PMID:29662619, PMID:31827405]. UBE2V1 also acts in Ubc13-independent or alternative contexts: it positively regulates K63-linked ubiquitinated protein aggregate formation, with cardiomyocyte- and oocyte-level consequences for proteostasis [PMID:32081062, PMID:40394227], partners with Smurf1 to degrade Smad1 [PMID:28771228], and with UBE2S can drive non-K63 (K11/K48) ubiquitination affecting VHL and Cyclin A turnover [PMID:41446875, PMID:41879050].","teleology":[{"year":1998,"claim":"Established that UEV proteins are catalytically dead E2 variants, reframing UBE2V1 from a presumptive enzyme to a regulatory cofactor with cell-cycle consequences.","evidence":"In vitro ubiquitin conjugation/transfer assays and gain-of-function overexpression in HT-29-M6 cells","pmids":["9418904"],"confidence":"High","gaps":["Did not identify the partner E2 that supplies catalytic activity","Mechanism linking UEV expression to Cdk1 inhibition unresolved"]},{"year":1998,"claim":"Cross-species complementation showed UEV function is conserved, implicating it in DNA-damage tolerance and transcriptional activation before its biochemical partner was known.","evidence":"Yeast mms2/YGL087c deletion complementation, DNA damage sensitivity, and c-fos-CAT reporter assays","pmids":["9580084","9705497"],"confidence":"Medium","gaps":["Did not distinguish direct versus indirect contributions to transcription","Partner requirements not defined"]},{"year":2003,"claim":"Placed Ubc13/Uev1A in the TNF→TRAF2→SAPK/JNK axis, linking K63 chain assembly to a defined signaling cascade.","evidence":"Dominant-negative Ubc13, siRNA, reciprocal co-IP of TRAF2/GCKR, and kinase activity assays","pmids":["12591926"],"confidence":"High","gaps":["Did not resolve which ubiquitination events are direct substrates versus chain extension"]},{"year":2005,"claim":"Demonstrated that the Uev partner determines Ubc13 pathway selectivity—Uev1A for NF-κB, Mms2 for DNA repair—and tunes chain length.","evidence":"In vitro chain-length assays, RNAi knockdown, NF-κB reporters, and DNA damage survival assays","pmids":["16129784"],"confidence":"High","gaps":["Structural basis for the partner-specific divergence not yet defined"]},{"year":2006,"claim":"Defined the structural mechanism by which Uev1A positions the acceptor ubiquitin for K63 linkage.","evidence":"NMR structure of hUev1a, interaction mapping, and restrained MD modeling of the Ub-Uev1a-Ubc13-Ub tetramer","pmids":["16893187"],"confidence":"High","gaps":["Model is computational for the tetramer; no high-resolution co-crystal of the full assembly"]},{"year":2007,"claim":"Dissected chain assembly into a Uev1A-independent substrate-priming step and a Uev1A-dependent elongation step.","evidence":"In vitro reconstitution with UBC13-UEV1A and TRAF6","pmids":["17709375"],"confidence":"High","gaps":["In vitro system; in-cell partitioning of priming versus elongation not measured"]},{"year":2006,"claim":"Showed UBE2V1 overexpression alone is sufficient to drive NF-κB activity and an anti-apoptotic, pro-survival phenotype.","evidence":"Stable overexpression, NF-κB luciferase reporter, Bcl-2 Western blot, and RNAi rescue in human cells","pmids":["17041755"],"confidence":"Medium","gaps":["Direct E3/substrate steps connecting UBE2V1 to Bcl-2 induction not mapped"]},{"year":2012,"claim":"Validated the Ubc13-Uev1A complex as a druggable node by blocking thioester formation to suppress NF-κB-dependent tumor survival.","evidence":"Small-molecule inhibitor (NSC697923) thioester assay, NF-κB reporter, and DLBCL viability with genetic knockdown","pmids":["22791293"],"confidence":"High","gaps":["Inhibitor selectivity against other thioester-forming E2s not fully characterized"]},{"year":2010,"claim":"Extended UBE2V1 function to membrane-receptor trafficking via an ortholog, linking K63 ubiquitination to endosomal sorting of glutamate receptors.","evidence":"C. elegans forward genetic screen, GLR-1::GFP imaging, ubc-13 epistasis, and UEV-1/UBC-13 co-IP","pmids":["21179194"],"confidence":"Medium","gaps":["E3 ligase and direct substrate in the trafficking step not identified","Conservation of this role in mammals untested in this corpus"]},{"year":2017,"claim":"Revealed Ubc13-independent and feedback-regulatory functions: degradation of Smad1 with Smurf1 and K63-modification of RHBDF2 to attenuate TNF signaling.","evidence":"Co-IP, K63-ubiquitination and TACE maturation assays, with Smad1/RHBDF2 readouts","pmids":["28771228","29069608"],"confidence":"Medium","gaps":["Single-lab co-IP evidence for each partnership","Switch between Ubc13-dependent and -independent modes not mechanistically defined"]},{"year":2018,"claim":"Connected UBE2V1 to epigenetic and metastatic programs through Sirt1 degradation and NF-κB-driven chemokine/protease effectors.","evidence":"Mass spectrometry, ubiquitination assays, and xenograft models in colorectal and breast cancer (Sirt1, CXCL1, MMP1)","pmids":["30016968","29662619","25022892"],"confidence":"Medium","gaps":["Direct versus indirect contribution to each effector not separated","Effects observed largely in overexpression/knockdown settings"]},{"year":2019,"claim":"Implicated UBE2V1 in AKT-axis survival and chemoresistance beyond NF-κB, including a CT45A-dependent migration program.","evidence":"Bidirectional genetic manipulation with AKT-FOXO1-BIM and CT45A readouts in breast cancer cells","pmids":["31827405","34503444"],"confidence":"Medium","gaps":["Biochemical link between UBE2V1 ubiquitination activity and AKT activation undefined"]},{"year":2020,"claim":"Defined the N-terminal extension as the molecular determinant that confers Uev1A-specific NF-κB activity, separating it from Mms2.","evidence":"In vitro polyubiquitination, thermodynamic binding measurements, and chimeric/truncation domain swaps with NF-κB reporters","pmids":["32659264"],"confidence":"High","gaps":["How the N-terminus mechanically enhances chain assembly at atomic resolution unresolved"]},{"year":2020,"claim":"Established UBE2V1 as a positive regulator of K63-linked protein aggregate formation with in vivo proteostasis and cardiac consequences.","evidence":"Cardiomyocyte overexpression/knockdown, UPS reporter, and AAV9-CRISPR cardiomyocyte-specific knockout in mice","pmids":["32081062"],"confidence":"High","gaps":["E3 partners and substrates driving aggregate formation not identified"]},{"year":2020,"claim":"Confirmed the conserved heterodimerization interface and dual repair/neurological roles using the Drosophila ortholog.","evidence":"Co-IP with F15E/F15Y mutagenesis, yeast complementation, DNA-damage sensitivity, and fly behavioral analysis","pmids":["32702441"],"confidence":"Medium","gaps":["Relevance of the neurological phenotype to mammalian UBE2V1 untested in this corpus"]},{"year":2025,"claim":"Uncovered non-canonical, non-K63 proteolytic functions of UBE2V1 acting with UBE2S to control VHL/HIF-1α and APC/C-dependent Cyclin A turnover.","evidence":"Co-IP, K11/K48-specific and Cyclin A degradation assays, HIF-1α reporter, Drosophila APC/C screen, and xenografts","pmids":["41446875","41879050"],"confidence":"Medium","gaps":["How UBE2V1 switches between K63 and K11/K48 chain types not mechanistically resolved","Single studies per claim"]},{"year":2025,"claim":"Linked UBE2V1-driven aggregate regulation to reproductive aging via oocyte aggresome dynamics.","evidence":"Advanced maternal age mouse model, oocyte overexpression/knockdown, and aggresome/maturation readouts","pmids":["40394227"],"confidence":"Medium","gaps":["Directionality of UBE2V1's effect on aggresomes appears context-dependent and is not reconciled with cardiomyocyte data","Substrates in oocytes unidentified"]},{"year":null,"claim":"The molecular switch governing how UBE2V1 selects between Ubc13-dependent K63 chain elongation, Ubc13-independent E3 partnerships, and UBE2S-dependent K11/K48 proteolytic ubiquitination remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or biochemical model unifying the distinct chain-type and partner choices","Substrate specificity determinants across contexts unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,4,6,8,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,11]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5,12]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,9,18,22]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,8,12]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[19,20]}],"complexes":["Ubc13-Uev1A E2 complex"],"partners":["UBE2N","TRAF2","RHBDF2","SMURF1","UBE2S","VHL","TRAF6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13404","full_name":"Ubiquitin-conjugating enzyme E2 variant 1","aliases":["CROC-1","TRAF6-regulated IKK activator 1 beta Uev1A"],"length_aa":147,"mass_kda":16.5,"function":"Has no ubiquitin ligase activity on its own. The UBE2V1-UBE2N heterodimer catalyzes the synthesis of non-canonical poly-ubiquitin chains that are linked through Lys-63. This type of poly-ubiquitination activates IKK and does not seem to involve protein degradation by the proteasome. Plays a role in the activation of NF-kappa-B mediated by IL1B, TNF, TRAF6 and TRAF2. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage. Promotes TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked polyubiquitin chains which activate the MAP3K7/TAK1 complex which in turn results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes. Together with RNF135 and UBE2N, catalyzes the viral RNA-dependent 'Lys-63'-linked polyubiquitination of RIGI to activate the downstream signaling pathway that leads to interferon beta production (PubMed:31006531). UBE2V1-UBE2N together with TRAF3IP2 E3 ubiquitin ligase mediate 'Lys-63'-linked polyubiquitination of TRAF6, a component of IL17A-mediated signaling pathway","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13404/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/UBE2V1","classification":"Common Essential","n_dependent_lines":722,"n_total_lines":1208,"dependency_fraction":0.597682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UBE2V1","total_profiled":1310},"omim":[{"mim_id":"616869","title":"C-TERMINAL DOMAIN NUCLEAR ENVELOPE PHOSPHATASE 1 REGULATORY SUBUNIT 1; CNEP1R1","url":"https://www.omim.org/entry/616869"},{"mim_id":"616017","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 69; TRIM69","url":"https://www.omim.org/entry/616017"},{"mim_id":"610994","title":"PLASMANYLETHANOLAMINE DESATURASE 1; PEDS1","url":"https://www.omim.org/entry/610994"},{"mim_id":"610432","title":"RING FINGER PROTEIN 125; RNF125","url":"https://www.omim.org/entry/610432"},{"mim_id":"603679","title":"UBIQUITIN-CONJUGATING ENZYME E2 N; UBE2N","url":"https://www.omim.org/entry/603679"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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to distinct cellular processes through physical interaction.\",\n      \"method\": \"In vitro polyubiquitination assays, functional complementation, RNA interference knockdown, NF-κB reporter assays, DNA damage survival assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (in vitro chain-length assays, genetic complementation, RNAi knockdown, functional pathway assays), findings replicated across distinct cellular readouts\",\n      \"pmids\": [\"16129784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TNF-induced activation of GCKR and the SAPK/JNK pathway requires the E2 complex Ubc13/Uev1A and the E3 TRAF2; TNF signaling leads to TRAF2 polyubiquitination and oligomerization and to GCKR ubiquitination and activation, all sensitive to disruption of Ubc13 function.\",\n      \"method\": \"Dominant-negative interference with Ubc13, siRNA knockdown of Ubc13, immunoprecipitation, kinase activity assays, co-immunoprecipitation of TRAF2 and GCKR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, dominant-negative and RNAi approaches, kinase activity readouts, multiple orthogonal experiments in one study\",\n      \"pmids\": [\"12591926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In an in vitro reconstituted system, UEV1A presents Lys63 of ubiquitin to suppress direct substrate modification while enabling Lys63-linked ubiquitin chain synthesis; protein modification with K63-linked chains occurs through a UEV1A-independent substrate modification step and a UEV1A-dependent chain-elongation mechanism.\",\n      \"method\": \"In vitro ubiquitination reconstitution assay with UBC13-UEV1A and TRAF6\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of enzymatic activity with defined components, mechanistic dissection of substrate vs. chain-building roles\",\n      \"pmids\": [\"17709375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NMR structure of hUev1a determined; hUev1a interacts with ubiquitin and hUbc13; a structural model of the Ub-hUev1a-hUbc13-Ub tetramer proposes that a hydrogen-bond network involving hUbc13-Asp81 and Ub-Glu64 positions Ub-Lys63 proximal to the active site for K63-linked chain synthesis.\",\n      \"method\": \"NMR spectroscopy, structural modeling, restrained molecular dynamics simulations\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure determination with interaction mapping and MD simulations; single lab but multiple orthogonal biophysical methods\",\n      \"pmids\": [\"16893187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"UEV-1 (UBE2V1/CROC-1) proteins lack the catalytic cysteine of E2 enzymes and are catalytically inactive in vitro (cannot conjugate or transfer ubiquitin to substrates); constitutive expression of UEV in HT-29-M6 cells inhibited differentiation upon confluence, caused G2-M accumulation, and inhibited the mitotic kinase Cdk1.\",\n      \"method\": \"In vitro ubiquitin conjugation/transfer assay, sequence analysis, cell cycle analysis by flow cytometry, constitutive overexpression in HT-29-M6 cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro enzymatic assay establishing catalytic inactivity, plus gain-of-function cell biology with defined molecular (Cdk1) readout\",\n      \"pmids\": [\"9418904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The small-molecule NSC697923 inhibits the Ubc13-Uev1A E2 complex by blocking formation of the Ubc13-ubiquitin thioester conjugate, thereby suppressing constitutive NF-κB activity and inhibiting proliferation and survival of DLBCL cells; Ubc13 knockdown similarly inhibited DLBCL cell survival.\",\n      \"method\": \"Small-molecule inhibitor screen, thioester conjugate formation assay, NF-κB reporter assay, siRNA knockdown, cell proliferation/survival assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical thioester assay, NF-κB reporter, and cell viability with both chemical inhibition and genetic knockdown, converging on same mechanism\",\n      \"pmids\": [\"22791293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Ube2v1 promotes Ubc13-mediated ubiquitination and proteasomal degradation of Sirt1, leading to inhibition of histone H4 lysine 16 acetylation and epigenetic suppression of autophagy gene expression, which promotes EMT and metastasis in colorectal cancer.\",\n      \"method\": \"Quantitative mass spectrometry, immunoprecipitation, ubiquitination assay, Western blotting, immunofluorescence, in vivo xenograft model\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay plus co-IP and in vivo rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30016968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Uev1A-Ubc13 complex promotes breast cancer cell invasion and metastasis through NF-κB activation and upregulation of MMP1; this process requires functional Ubc13 (physical interaction with Uev1A is necessary), and depletion of UEV1 reduces MMP1 expression and prevents tumor formation/metastasis in xenograft mice.\",\n      \"method\": \"Overexpression and siRNA knockdown in MDA-MB-231 cells, NF-κB reporter assay, invasion/migration assays, xenograft mouse model, MMP1 rescue experiment\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic manipulation (OE and KD), NF-κB pathway readout, in vivo xenograft, and downstream effector rescue; single lab\",\n      \"pmids\": [\"25022892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Uev1A-Ubc13 complex interacts with RHBDF2 and, upon TNFα stimulation cooperates with the E3 CHIP to promote K63-linked ubiquitination of RHBDF2, enhancing TACE maturation and subsequent shedding of the TNFα receptor to attenuate NF-κB signaling.\",\n      \"method\": \"Co-immunoprecipitation, K63-linked ubiquitination assay, TACE maturation assay, UEV1A overexpression and inhibition experiments\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, and functional TACE maturation readout; single lab, multiple methods\",\n      \"pmids\": [\"29069608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Uev1A promotes osteosarcoma differentiation by collaborating with the E3 ligase Smurf1 to promote ubiquitination and degradation of Smad1 (a BMP signaling effector), and this process occurs in a Ubc13-independent manner.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Western blotting, UEV1A overexpression and knockdown, Smad1 as downstream effector readout\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay with Ubc13-independent mechanistic determination; single lab\",\n      \"pmids\": [\"28771228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ube2v1 positively regulates K63-linked ubiquitination to promote protein aggregate formation in cardiomyocytes; Ube2v1 knockdown improves ubiquitin proteasome system performance and promotes degradation of insoluble ubiquitinated proteins without altering autophagic flux; cardiomyocyte-specific Ube2v1 knockout alleviates CryABR120G-induced protein aggregation, improves cardiac function, and prolongs lifespan in vivo.\",\n      \"method\": \"Adenoviral overexpression/knockdown in neonatal rat ventricular cardiomyocytes, UPS reporter assay, AAV9-CRISPR cardiomyocyte-specific knockout in mice, echocardiography, autophagic flux assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo cardiac-specific KO with functional cardiac readout plus mechanistic UPS reporter assay, multiple orthogonal approaches\",\n      \"pmids\": [\"32081062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The N-terminal extension of Uev1A (absent in Mms2) stimulates polyubiquitin chain assembly, weakens the Uev-Ubc13 interaction affinity, and is specifically required for NF-κB activation; a chimeric protein with the Uev1A N-terminus fused to Mms2 functionally resembles Uev1A, whereas truncated Uev1A lacking the N-terminal extension behaves like Mms2.\",\n      \"method\": \"In vitro polyubiquitination assay, thermodynamic binding measurements (ITC or equivalent), chimeric and truncation mutant functional assays, NF-κB reporter assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro enzymatic and thermodynamic assays combined with chimeric/truncation domain-swap analysis and cellular pathway readout; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"32659264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Constitutive high-level expression of UEV1A alone in human cells is sufficient to increase NF-κB activity, upregulate the anti-apoptotic protein Bcl-2, confer prolonged cell survival under serum deprivation, and protect against apoptosis from diverse stressing agents; all effects are reversible upon RNAi-mediated suppression of UEV1.\",\n      \"method\": \"Stable overexpression of UEV1A, NF-κB luciferase reporter assay, Western blotting, RNAi knockdown, cell survival/apoptosis assays\",\n      \"journal\": \"Apoptosis : an international journal on programmed cell death\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and RNAi rescue, NF-κB pathway readout, and Bcl-2 as downstream effector; single lab\",\n      \"pmids\": [\"17041755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Uev1A-Ubc13 promotes colorectal cancer metastasis through NF-κB activation and upregulation of CXCL1; UEV1A overexpression depends on its physical interaction with Ubc13 to promote invasion, and depletion of UEV1 reduces CXCL1 expression and prevents tumor growth in a xenograft model.\",\n      \"method\": \"Overexpression and siRNA knockdown in HCT116 cells, NF-κB reporter, invasion assay, xenograft mouse model, IHC of human samples\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — OE/KD with Ubc13-interaction dependency, NF-κB pathway and CXCL1 readout, in vivo xenograft; single lab\",\n      \"pmids\": [\"29662619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UEV1A promotes breast cancer cell survival under serum starvation and chemoresistance through activation of the AKT signaling pathway that in turn inhibits FOXO1 and BIM expression; depletion of UEV1 inhibits AKT signaling and promotes FOXO1/BIM expression, reducing cell survival and enhancing chemosensitivity.\",\n      \"method\": \"Overexpression and siRNA knockdown of UEV1A in MDA-MB-231 and MCF7 cells, Western blotting for AKT/FOXO1/BIM, cell viability and chemosensitivity assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation with defined pathway readouts (AKT-FOXO1-BIM); single lab\",\n      \"pmids\": [\"31827405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"C. elegans UEV-1 (ortholog of UBE2V1) regulates trafficking of the AMPA-type glutamate receptor GLR-1; loss of uev-1 causes GLR-1 accumulation in RAB-10-containing endosomes in neuron cell bodies and along neurites, independent of clathrin-mediated endocytosis; ubc-13 mutants phenocopy uev-1 mutants, and UEV-1 can physically interact with C. elegans UBC-13.\",\n      \"method\": \"Forward genetic screen in C. elegans, fluorescence imaging of GLR-1::GFP, behavioral reversal assay, genetic epistasis with ubc-13, co-immunoprecipitation of UEV-1 and UBC-13, K63-ubiquitin immunostaining\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen, fluorescence localization, epistasis with ubc-13, and co-IP; single lab but multiple orthogonal methods in C. elegans ortholog\",\n      \"pmids\": [\"21179194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UEV1A overexpression induces CT45A family gene expression in breast cancer cells and promotes cell migration and EMT signaling through the AKT pathway (independently of NF-κB); depletion of CT45A abolishes these effects, identifying CT45A as a critical downstream effector of Uev1A in AKT-dependent migration.\",\n      \"method\": \"UEV1A and CT45A overexpression/knockdown in breast cancer cells, gene expression profiling, cell migration assay, Western blotting for AKT and NF-κB pathway components\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation, pathway inhibitor analysis, and downstream effector rescue; single lab\",\n      \"pmids\": [\"34503444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Drosophila Uev1a forms a stable heterodimer with Bendless (Drosophila Ubc13 ortholog); Uev1a-F15E mutation abolishes this interaction, and Uev1a-F15Y severely reduces it; dUev1a functionally rescues yeast mms2 null mutants in a Bendless-dependent manner, and heterozygous dUev1a mutant flies show increased sensitivity to DNA-damaging agents and reduced mobility consistent with neurological defects.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (F15E, F15Y), yeast functional complementation, DNA damage sensitivity assay, Drosophila mutant behavioral analysis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mutagenesis, cross-species complementation, and in vivo Drosophila phenotypic readouts; single lab\",\n      \"pmids\": [\"32702441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UBE2V1 competes with HIF-1α for binding to the β-domain of VHL protein and, in complex with UBE2S, catalyzes K11/K48-linked ubiquitination of VHL at K196, leading to VHL proteasomal degradation, reduced HIF-1α ubiquitination, and sustained HIF-1α stabilization, creating a positive feedback loop in hepatocellular carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K11/K48-specific), UBE2V1 overexpression/knockdown, HIF-1α reporter assay, VHL degradation assay, in vivo xenograft\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, site-specific ubiquitination assay with defined lysine (K196), and functional HIF-1α stabilization readout; single lab\",\n      \"pmids\": [\"41446875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human UEV-1A cDNA fully complements the UV and MMS sensitivity of a yeast YGL087c deletion mutant, demonstrating functional conservation of UEV proteins in DNA damage tolerance across species.\",\n      \"method\": \"Yeast deletion mutant complementation assay, DNA damage sensitivity assay (UV and MMS)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cross-species functional complementation with defined genetic readout; single lab, single method\",\n      \"pmids\": [\"9580084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human UEV (CROC-1/hMMS2) genes complement yeast mms2 defects in DNA damage sensitivity and spontaneous mutagenesis, and both MMS2 and hMMS2 transactivate a c-fos-CAT reporter gene in mammalian cells, demonstrating functional conservation across species in both DNA repair and transcriptional activation.\",\n      \"method\": \"Yeast mms2 mutant complementation assay, transient co-transfection with c-fos-CAT reporter in Rat-1 cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cross-species genetic complementation and mammalian reporter assay; single lab, two independent functional readouts\",\n      \"pmids\": [\"9705497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UBE2V1 positively regulates ubiquitinated protein aggregate formation in mouse oocytes; UBE2V1 expression increases with maternal aging and correlates with aggresome formation; restoring UBE2V1 expression in aged oocytes/embryos alleviates aggresome formation and partly ameliorates age-related defects in oocyte maturation and embryo development.\",\n      \"method\": \"Mouse model of advanced maternal age, UBE2V1 overexpression/knockdown in oocytes, immunofluorescence for ubiquitinated aggregates/aggresomes, oocyte maturation and embryo development assessment\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation with defined cellular readouts (aggresome formation, oocyte maturation); single lab\",\n      \"pmids\": [\"40394227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Uev1A collaborates with the E3 APC/C complex to mediate proteasomal degradation of Cyclin A in Drosophila, representing a non-canonical (proteolytic) function; this protects polyploid nurse cells from oncogenic Ras-induced aberrant division stress; human UBE2V1 and UBE2V2 similarly counteract oncogenic Ras-driven tumorigenesis in vivo.\",\n      \"method\": \"Genome-wide genetic screen in Drosophila, genetic epistasis, Cyclin A degradation assay, xenograft tumor model in nude mice with human UBE2V1/UBE2V2 overexpression\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide screen, APC/C epistasis, Cyclin A degradation readout, and in vivo xenograft; published peer-reviewed, single study\",\n      \"pmids\": [\"41879050\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBE2V1 (Uev1A) is a catalytically inactive ubiquitin-conjugating enzyme variant that obligately heterodimerizes with Ubc13 to stimulate K63-linked polyubiquitin chain synthesis; the Uev1A–Ubc13 complex activates NF-κB (via TRAF2/TRAF6/NEMO ubiquitination), drives JNK/SAPK and AKT signaling, promotes K63-linked ubiquitination of substrates including RHBDF2 and Sirt1, and can also act in a Ubc13-independent manner (with Smurf1 to degrade Smad1 or with UBE2S/APC/C to degrade Cyclin A), with the unique N-terminal extension of Uev1A distinguishing its pro-NF-κB and polyubiquitin chain-assembly activity from the DNA-repair-directed Mms2–Ubc13 complex.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBE2V1 (Uev1A/CROC-1) is a catalytically inactive ubiquitin-conjugating enzyme variant that lacks the canonical E2 active-site cysteine and cannot itself transfer ubiquitin, instead functioning as a specificity-determining cofactor that obligately heterodimerizes with the E2 Ubc13 to direct synthesis of Lys63-linked polyubiquitin chains [#4, #0]. Within this complex, Ubc13 catalyzes thioester-linked ubiquitin transfer while UBE2V1 binds and positions the acceptor ubiquitin so that its Lys63 lies proximal to the active site, enabling processive chain elongation distinct from the UBE2V1-independent initial substrate-modification step [#2, #3]. A unique N-terminal extension absent from the paralog Mms2 stimulates chain assembly, weakens the Uev-Ubc13 affinity, and specifically routes the complex toward NF-\\u03baB activation rather than DNA-damage tolerance, explaining why Ubc13-Uev1A drives inflammatory signaling while Ubc13-Mms2 serves DNA repair [#11, #0]. Functionally, Ubc13-Uev1A operates downstream of TNF through TRAF2 polyubiquitination to activate JNK/SAPK signaling [#1] and is sufficient on its own to elevate NF-\\u03baB activity, upregulate Bcl-2, and confer apoptotic resistance [#12]; this activity is pharmacologically tractable, as the inhibitor NSC697923 blocks Ubc13~ubiquitin thioester formation and suppresses NF-\\u03baB-dependent lymphoma survival [#5]. Through NF-\\u03baB- and AKT-driven programs, UBE2V1 promotes cancer cell invasion, metastasis, and chemoresistance via effectors including MMP1, CXCL1, and AKT-FOXO1-BIM signaling [#7, #13, #14]. UBE2V1 also acts in Ubc13-independent or alternative contexts: it positively regulates K63-linked ubiquitinated protein aggregate formation, with cardiomyocyte- and oocyte-level consequences for proteostasis [#10, #21], partners with Smurf1 to degrade Smad1 [#9], and with UBE2S can drive non-K63 (K11/K48) ubiquitination affecting VHL and Cyclin A turnover [#18, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that UEV proteins are catalytically dead E2 variants, reframing UBE2V1 from a presumptive enzyme to a regulatory cofactor with cell-cycle consequences.\",\n      \"evidence\": \"In vitro ubiquitin conjugation/transfer assays and gain-of-function overexpression in HT-29-M6 cells\",\n      \"pmids\": [\"9418904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the partner E2 that supplies catalytic activity\", \"Mechanism linking UEV expression to Cdk1 inhibition unresolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Cross-species complementation showed UEV function is conserved, implicating it in DNA-damage tolerance and transcriptional activation before its biochemical partner was known.\",\n      \"evidence\": \"Yeast mms2/YGL087c deletion complementation, DNA damage sensitivity, and c-fos-CAT reporter assays\",\n      \"pmids\": [\"9580084\", \"9705497\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not distinguish direct versus indirect contributions to transcription\", \"Partner requirements not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placed Ubc13/Uev1A in the TNF\\u2192TRAF2\\u2192SAPK/JNK axis, linking K63 chain assembly to a defined signaling cascade.\",\n      \"evidence\": \"Dominant-negative Ubc13, siRNA, reciprocal co-IP of TRAF2/GCKR, and kinase activity assays\",\n      \"pmids\": [\"12591926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which ubiquitination events are direct substrates versus chain extension\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that the Uev partner determines Ubc13 pathway selectivity\\u2014Uev1A for NF-\\u03baB, Mms2 for DNA repair\\u2014and tunes chain length.\",\n      \"evidence\": \"In vitro chain-length assays, RNAi knockdown, NF-\\u03baB reporters, and DNA damage survival assays\",\n      \"pmids\": [\"16129784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for the partner-specific divergence not yet defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the structural mechanism by which Uev1A positions the acceptor ubiquitin for K63 linkage.\",\n      \"evidence\": \"NMR structure of hUev1a, interaction mapping, and restrained MD modeling of the Ub-Uev1a-Ubc13-Ub tetramer\",\n      \"pmids\": [\"16893187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Model is computational for the tetramer; no high-resolution co-crystal of the full assembly\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Dissected chain assembly into a Uev1A-independent substrate-priming step and a Uev1A-dependent elongation step.\",\n      \"evidence\": \"In vitro reconstitution with UBC13-UEV1A and TRAF6\",\n      \"pmids\": [\"17709375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro system; in-cell partitioning of priming versus elongation not measured\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed UBE2V1 overexpression alone is sufficient to drive NF-\\u03baB activity and an anti-apoptotic, pro-survival phenotype.\",\n      \"evidence\": \"Stable overexpression, NF-\\u03baB luciferase reporter, Bcl-2 Western blot, and RNAi rescue in human cells\",\n      \"pmids\": [\"17041755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct E3/substrate steps connecting UBE2V1 to Bcl-2 induction not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Validated the Ubc13-Uev1A complex as a druggable node by blocking thioester formation to suppress NF-\\u03baB-dependent tumor survival.\",\n      \"evidence\": \"Small-molecule inhibitor (NSC697923) thioester assay, NF-\\u03baB reporter, and DLBCL viability with genetic knockdown\",\n      \"pmids\": [\"22791293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Inhibitor selectivity against other thioester-forming E2s not fully characterized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended UBE2V1 function to membrane-receptor trafficking via an ortholog, linking K63 ubiquitination to endosomal sorting of glutamate receptors.\",\n      \"evidence\": \"C. elegans forward genetic screen, GLR-1::GFP imaging, ubc-13 epistasis, and UEV-1/UBC-13 co-IP\",\n      \"pmids\": [\"21179194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase and direct substrate in the trafficking step not identified\", \"Conservation of this role in mammals untested in this corpus\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed Ubc13-independent and feedback-regulatory functions: degradation of Smad1 with Smurf1 and K63-modification of RHBDF2 to attenuate TNF signaling.\",\n      \"evidence\": \"Co-IP, K63-ubiquitination and TACE maturation assays, with Smad1/RHBDF2 readouts\",\n      \"pmids\": [\"28771228\", \"29069608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab co-IP evidence for each partnership\", \"Switch between Ubc13-dependent and -independent modes not mechanistically defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected UBE2V1 to epigenetic and metastatic programs through Sirt1 degradation and NF-\\u03baB-driven chemokine/protease effectors.\",\n      \"evidence\": \"Mass spectrometry, ubiquitination assays, and xenograft models in colorectal and breast cancer (Sirt1, CXCL1, MMP1)\",\n      \"pmids\": [\"30016968\", \"29662619\", \"25022892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect contribution to each effector not separated\", \"Effects observed largely in overexpression/knockdown settings\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Implicated UBE2V1 in AKT-axis survival and chemoresistance beyond NF-\\u03baB, including a CT45A-dependent migration program.\",\n      \"evidence\": \"Bidirectional genetic manipulation with AKT-FOXO1-BIM and CT45A readouts in breast cancer cells\",\n      \"pmids\": [\"31827405\", \"34503444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical link between UBE2V1 ubiquitination activity and AKT activation undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the N-terminal extension as the molecular determinant that confers Uev1A-specific NF-\\u03baB activity, separating it from Mms2.\",\n      \"evidence\": \"In vitro polyubiquitination, thermodynamic binding measurements, and chimeric/truncation domain swaps with NF-\\u03baB reporters\",\n      \"pmids\": [\"32659264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the N-terminus mechanically enhances chain assembly at atomic resolution unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established UBE2V1 as a positive regulator of K63-linked protein aggregate formation with in vivo proteostasis and cardiac consequences.\",\n      \"evidence\": \"Cardiomyocyte overexpression/knockdown, UPS reporter, and AAV9-CRISPR cardiomyocyte-specific knockout in mice\",\n      \"pmids\": [\"32081062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 partners and substrates driving aggregate formation not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed the conserved heterodimerization interface and dual repair/neurological roles using the Drosophila ortholog.\",\n      \"evidence\": \"Co-IP with F15E/F15Y mutagenesis, yeast complementation, DNA-damage sensitivity, and fly behavioral analysis\",\n      \"pmids\": [\"32702441\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relevance of the neurological phenotype to mammalian UBE2V1 untested in this corpus\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered non-canonical, non-K63 proteolytic functions of UBE2V1 acting with UBE2S to control VHL/HIF-1\\u03b1 and APC/C-dependent Cyclin A turnover.\",\n      \"evidence\": \"Co-IP, K11/K48-specific and Cyclin A degradation assays, HIF-1\\u03b1 reporter, Drosophila APC/C screen, and xenografts\",\n      \"pmids\": [\"41446875\", \"41879050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How UBE2V1 switches between K63 and K11/K48 chain types not mechanistically resolved\", \"Single studies per claim\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked UBE2V1-driven aggregate regulation to reproductive aging via oocyte aggresome dynamics.\",\n      \"evidence\": \"Advanced maternal age mouse model, oocyte overexpression/knockdown, and aggresome/maturation readouts\",\n      \"pmids\": [\"40394227\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directionality of UBE2V1's effect on aggresomes appears context-dependent and is not reconciled with cardiomyocyte data\", \"Substrates in oocytes unidentified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular switch governing how UBE2V1 selects between Ubc13-dependent K63 chain elongation, Ubc13-independent E3 partnerships, and UBE2S-dependent K11/K48 proteolytic ubiquitination remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural or biochemical model unifying the distinct chain-type and partner choices\", \"Substrate specificity determinants across contexts unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 4, 6, 8, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 11]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5, 12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 9, 18, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 8, 12]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [19, 20]}\n    ],\n    \"complexes\": [\"Ubc13-Uev1A E2 complex\"],\n    \"partners\": [\"UBE2N\", \"TRAF2\", \"RHBDF2\", \"SMURF1\", \"UBE2S\", \"VHL\", \"TRAF6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}