{"gene":"UBE2T","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2006,"finding":"UBE2T is the E2 ubiquitin-conjugating enzyme essential for the Fanconi anemia pathway; it binds to FANCL (the E3 ubiquitin ligase subunit of the FA core complex) and is required for monoubiquitination of FANCD2 in vivo. UBE2T also undergoes automonoubiquitination stimulated by FANCL, which inactivates UBE2T, providing a self-inactivation/negative regulatory mechanism.","method":"Co-immunoprecipitation, in vivo ubiquitination assays, siRNA knockdown with chromosomal aberration readout, autoubiquitination assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo ubiquitination, loss-of-function phenotype; foundational paper replicated by multiple subsequent studies","pmids":["16916645"],"is_preprint":false},{"year":2008,"finding":"In vitro reconstitution of FANCD2 monoubiquitination requires minimally UBE2T and FANCL. A conserved RWD-like domain in FANCL stimulates monoubiquitination. Addition of FANCI enhances monoubiquitination and restricts it to the in vivo substrate lysine residue on FANCD2 (K561).","method":"In vitro reconstitution of ubiquitination reaction with purified components; domain mutagenesis of FANCL; addition of recombinant FANCI","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro with purified proteins, mechanistic dissection of domain requirements, replicated in subsequent studies","pmids":["19111657"],"is_preprint":false},{"year":2007,"finding":"UBE2T and FANCD2 are each recruited to chromatin independently of the FA core complex. The E3 ligase activity of the FA core complex is determined not by its stable assembly but by its DNA damage-induced localization to chromatin. Therefore, FANCD2 monoubiquitination is regulated by formation of an active E2/E3 holoenzyme on chromatin rather than by multiprotein complex assembly.","method":"Chromatin fractionation, cell biology epistasis experiments dissociating core complex assembly from E3 activity, subcellular localization studies","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — chromatin fractionation with functional dissection, multiple independent genetic dissections, replicated logic in subsequent studies","pmids":["17938197"],"is_preprint":false},{"year":2009,"finding":"FANCI is monoubiquitinated on Lys-523 by the UBE2T–FANCL pair in vitro. FANCI and its C-terminal fragment possess a DNA binding activity that prefers branched DNA structures.","method":"In vitro ubiquitination assay with purified UBE2T and FANCL; DNA binding assay with branched DNA substrates","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of FANCI monoubiquitination with site identification; single lab but orthogonal biochemical assays","pmids":["19589784"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of the FANCL RING domain in complex with UBE2T revealed a specific and extensive network of electrostatic and hydrophobic interactions beyond the generic E2–E3 interface that determines selective recognition of UBE2T over other E2 enzymes by FANCL.","method":"X-ray crystallography of FANCL RING–UBE2T complex; mutagenesis to confirm specificity-determining interactions","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution crystal structure with mutagenesis validation; single lab but rigorous structural method","pmids":["24389026"],"is_preprint":false},{"year":2012,"finding":"UBE2T (and FANCM) are required for nucleotide excision repair (NER) in addition to their role in ICL repair. UBE2T-deficient DT40 cells are unexpectedly sensitive to UV-induced DNA damage; genetic epistasis experiments indicate UBE2T collaborates to promote NER rather than translesion bypass, and UBE2T deficiency impairs efficient removal of UV-induced cyclobutane pyrimidine dimers.","method":"DT40 cell knockouts, UV sensitivity assays, genetic epistasis (double-mutant analysis), photolesion removal assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic knockouts with epistasis in avian model, photolesion removal assay; single lab","pmids":["22615860"],"is_preprint":false},{"year":2015,"finding":"Biallelic loss-of-function mutations in UBE2T cause Fanconi anemia (FA-T subtype). Patient fibroblasts lack FANCD2 and FANCI monoubiquitination, fail to form FANCD2 foci after MMC treatment, and are hypersensitive to crosslinking agents; these defects are complemented by wild-type UBE2T expression. A missense mutation (p.Gln2Glu) abolishes FANCD2 monoubiquitination and FANCL interaction.","method":"Patient cell complementation assays, western blot for monoubiquitination, immunofluorescence for FANCD2 foci, crosslinker hypersensitivity assays, Co-IP for FANCL interaction","journal":"Cell reports / American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent patient cohorts, complementation assays, Co-IP, and functional readouts across three independent papers","pmids":["26119737","26046368","26085575"],"is_preprint":false},{"year":2019,"finding":"CaMKII-δ9 phosphorylates UBE2T and targets it for degradation, thereby disrupting UBE2T-dependent DNA repair, causing accumulation of DNA damage and genome instability in cardiomyocytes, and promoting cardiomyopathy and heart failure.","method":"Kinase assay (CaMKII-δ9 phosphorylation of UBE2T), protein degradation assays, cardiac-specific overexpression and knockout mouse models, DNA damage readouts","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — kinase-substrate relationship demonstrated, in vivo mouse models with cardiac phenotype, multiple orthogonal methods","pmids":["31481791"],"is_preprint":false},{"year":2011,"finding":"Hypoxia rapidly and potently reduces UBE2T mRNA levels in cancer cell lines through reduced promoter activity (HIF-independent, not due to mRNA or protein stability changes), correlating with increased sensitivity to interstrand crosslinking agents and disruption of the FA pathway.","method":"Microarray, qPCR, western blot, HIF knockdown cell lines, RCC4 constitutive HIF1α cells, promoter activity assays, MMC survival assays","journal":"Radiotherapy and oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple gene expression methods plus promoter activity assay and HIF independence established; single lab","pmids":["21722982"],"is_preprint":false},{"year":2017,"finding":"A novel allosteric binding pocket on UBE2T was identified through fragment screening; fragments binding to this site inhibit ubiquitin conjugation in vitro.","method":"Fragment screening by biophysical methods (SPR, DSF), in vitro ubiquitin conjugation inhibition assays","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with structural fragment binding; single lab, allosteric site confirmed biochemically","pmids":["28437106"],"is_preprint":false},{"year":2017,"finding":"A zinc ion from a fragment library contaminant binds the active-site cysteine of UBE2T and induces a domain swap leading to cyclic trimerization in an open-ended linear assembly, revealing structural plasticity of the UBE2T active site.","method":"Co-crystal structure (X-ray crystallography), biophysical characterization (SPR/DSF), biochemical assays","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure with clear mechanistic insight; single study, single lab","pmids":["28933844"],"is_preprint":false},{"year":2019,"finding":"A small-molecule inhibitor of UBE2T/FANCL-mediated FANCD2 monoubiquitylation was identified that sensitizes cells to the DNA cross-linking agent carboplatin, establishing UBE2T enzymatic activity as pharmacologically targetable.","method":"High-throughput screen-compatible in vitro ubiquitylation assay; cell sensitization to carboplatin","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay plus cellular phenotype; single lab, two orthogonal methods","pmids":["31525021"],"is_preprint":false},{"year":2020,"finding":"UBE2T forms an E2–E3 pair with RNF8 and monoubiquitinates histone variant H2AX/γH2AX upon radiation exposure. This monoubiquitination facilitates CHK1 phosphorylation/activation and CHK1 release from chromatin to cytosol. E2-enzyme-deficient mutation C86A of UBE2T and monoubiquitination-site-deficient mutation K119/120R of H2AX both abrogate CHK1 activation.","method":"Co-immunoprecipitation (UBE2T–RNF8 E2–E3 pair), chromatin fractionation, immunofluorescence, active-site mutagenesis (C86A), substrate site mutagenesis (K119/120R H2AX), CHK1 phosphorylation assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for E2–E3 identification, active-site and substrate-site mutagenesis, chromatin fractionation; single lab with multiple orthogonal methods","pmids":["33087136"],"is_preprint":false},{"year":2020,"finding":"UBE2T promotes Wnt/β-catenin signaling hyperactivation in gastric cancer by mediating ubiquitination and proteasomal degradation of RACK1 at lysine residues K172, K225, and K257, independently of an E3 ligase.","method":"Ubiquitination assays, site-directed mutagenesis of RACK1 lysine residues, proteasome inhibitor experiments, Co-IP, small-molecule inhibitor (M435-1279) functional studies","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination site mapping by mutagenesis, E3-independent activity demonstrated biochemically; single lab, multiple methods","pmids":["33323973"],"is_preprint":false},{"year":2020,"finding":"UBE2T promotes ubiquitination and degradation of FOXO1 in non-small cell lung cancer, activating Wnt/β-catenin signaling, and promoting EMT and radiation resistance.","method":"Co-immunoprecipitation, RNA-Seq, western blot, colony formation, flow cytometry, in vivo xenograft","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP for interaction, ubiquitination implied by protein level changes; mechanistic follow-up is partial in abstract","pmids":["32590022"],"is_preprint":false},{"year":2017,"finding":"UBE2T promotes ubiquitination and degradation of p53, decreasing p53, p21, and Noxa levels, thereby facilitating hepatocellular carcinoma cell growth.","method":"Western blot, ectopic overexpression and knockdown, ubiquitination assay of p53","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, ubiquitination assay of p53 shown but limited mechanistic detail in abstract; replicated in other cancer contexts","pmids":["28935368"],"is_preprint":false},{"year":2022,"finding":"UBE2T promotes K63-linked ubiquitination of Akt, activating Akt/β-catenin signaling; E2-enzyme-deficient mutation C86A of UBE2T and ubiquitination-site-deficient mutation K8/14R of Akt impair downstream pathway activation and pyrimidine enzyme upregulation in HCC.","method":"Co-immunoprecipitation, K63-specific ubiquitination assay, active-site mutagenesis (C86A UBE2T), substrate mutagenesis (K8/14R Akt), LC/MS-MS metabolomics, in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — active-site and substrate-site mutagenesis with functional readout, K63 linkage specificity established; single lab, multiple orthogonal methods","pmids":["35169125"],"is_preprint":false},{"year":2021,"finding":"UBE2T physically binds the E3 ubiquitin ligase Mule and regulates its protein level via ubiquitination, thereby preventing Mule-mediated degradation of β-catenin and promoting liver CSC functions. This effect requires the E2 catalytic activity of UBE2T.","method":"Co-immunoprecipitation, ubiquitination assay, E2-activity-impaired mutant, β-catenin degradation assays, sphere formation and tumorigenicity assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct binding, ubiquitination assay, E2 activity mutant confirmation; single lab, multiple methods","pmids":["33542213"],"is_preprint":false},{"year":2021,"finding":"NEDD4L is an E3 ligase that ubiquitinates UBE2T and targets it for proteasomal degradation, reducing UBE2T protein half-life; NEDD4L-mediated UBE2T degradation represses PI3K-AKT signaling and suppresses lung adenocarcinoma cell progression.","method":"Half-life analysis, in vivo ubiquitylation assay, NEDD4L overexpression/depletion, Co-IP, xenograft models","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — E3 ubiquitin ligase-substrate relationship with half-life and in vivo ubiquitination assay; single lab, multiple methods","pmids":["34838005"],"is_preprint":false},{"year":2020,"finding":"SENP1 deSUMOylates UBE2T, increasing UBE2T protein expression and activating the Akt pathway, promoting HCC progression. UBE2T is thus identified as a SUMOylation substrate regulated by SENP1.","method":"SENP1 knockout model, Co-IP, deSUMOylation assay, western blot, in vitro and in vivo tumor assays","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and deSUMOylation assay shown; single lab, limited mechanistic detail in abstract","pmids":["31969492"],"is_preprint":false},{"year":2023,"finding":"UBE2T catalyzes RING1-mediated ubiquitination of p53, relieving transcriptional repression of ribonucleotide reductase subunits RRM1 and RRM2, resulting in unrestrained pyrimidine biosynthesis and alleviation of replication stress in pancreatic cancer, conferring gemcitabine resistance.","method":"Spontaneous KPC Ube2t-conditional knockout mice, organoids, PDX, proteomics, metabolomics, transcriptional reporter assays","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional knockout with survival benefit, combined proteomics and metabolomics; single lab, multiple orthogonal methods","pmids":["36842710"],"is_preprint":false},{"year":2022,"finding":"UBE2T directly binds FANCI and regulates its monoubiquitination; overexpression of UBE2T reversed effects of FANCI knockdown in NSCLC cells, placing UBE2T upstream of FANCI monoubiquitination in a cancer context.","method":"Co-immunoprecipitation confirming UBE2T–FANCI direct binding, monoubiquitination assay, rescue experiments","journal":"Oncology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with partial follow-up; single lab","pmids":["35703356"],"is_preprint":false},{"year":2022,"finding":"UBE2T mediates K48-linked polyubiquitination and degradation of ribosomal protein L6 (RPL6) in an E3 ligase-independent manner in glioblastoma, reducing wild-type p53 and enhancing gain-of-function mutant p53.","method":"Co-immunoprecipitation, ubiquitination assay with K48 linkage specificity, in vitro and in vivo GBM models","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, K48 linkage demonstrated but E3-independence claim has limited mechanistic validation in abstract","pmids":["36156329"],"is_preprint":false},{"year":2023,"finding":"UBE2T resolves R-loops and stabilizes replication forks at transcription-replication conflict sites and common fragile sites in primordial germ cells (PGCs), and promotes mitotic DNA synthesis to maintain genome stability; Ube2t knockout mice show defects in PGC proliferation with DNA damage accumulation and p53 pathway activation.","method":"Ube2t knockout mice, R-loop detection assays, replication fork stability assays, DNA damage markers, p53 pathway activation readouts","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout with multiple mechanistic readouts; single lab, clean genetic model with multiple cellular phenotypes","pmids":["36928776"],"is_preprint":false},{"year":2019,"finding":"CRISPR/Cas9-mediated knockout of UBE2T in HeLa and U2OS cells only partially reduced homologous recombination (HR), demonstrating that UBE2T-independent pathways can compensate for the recombination defect in UBE2T/FANCT null cells.","method":"CRISPR/Cas9 knockout, fluorescent reporter recombination assay, HR quantification","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean CRISPR knockout with quantitative HR reporter assay; negative/partial result rigorously established in single lab","pmids":["30715513"],"is_preprint":false},{"year":2024,"finding":"Fragment screening by 19F-NMR and 1H-15N-HSQC, validated by X-ray crystallography, identified two new binding pockets on UBE2T distinct from the active site; compounds binding these sites show inhibitory activity on UBE2T ubiquitination.","method":"19F-NMR fragment screening, 1H-15N-HSQC NMR validation, X-ray co-crystal structures, in vitro UBE2T activity assays","journal":"Protein science","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR and X-ray structure with functional inhibition assay; single lab, multiple orthogonal biophysical methods","pmids":["38358126"],"is_preprint":false},{"year":2025,"finding":"UBE2T mediates K48-linked polyubiquitination and proteasomal degradation of CDC42, thereby preventing CDC42-mediated autophagic lysosomal degradation of CD276 (B7-H3), leading to CD276 upregulation, impairment of CD8+ T cell function, and immune escape in triple-negative breast cancer.","method":"Co-IP, GST pull-down, mass spectrometry, western blot, ubiquitination assay (K48-linkage), flow cytometry, immunofluorescence, in vivo models","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and GST pulldown for direct interaction, K48 linkage specificity, multiple orthogonal methods; single lab","pmids":["39915000"],"is_preprint":false},{"year":2024,"finding":"UBE2T collaborates with E3 ligase TRIM25 to perform K48-linked polyubiquitination and degradation of CBX6 at K214, relieving transcriptional repression of pluripotency genes SOX2 and NANOG and enhancing breast cancer stem cell stemness.","method":"Co-IP, in vivo ubiquitination assay (K48-specific), site mutagenesis (K214R CBX6), spontaneous MMTV-PyMT mouse model, organoids, scRNA-seq","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination with linkage and site specificity, in vivo genetic model; single lab, multiple orthogonal methods","pmids":["39716485"],"is_preprint":false},{"year":2025,"finding":"UBE2T mediates ubiquitination-dependent degradation of HP1α via the proteasome pathway in IDH1/TP53-mutant glioma, leading to release of suppressive effects of R-2-hydroxyglutarate on nucleolar function and increased rDNA transcription.","method":"Co-IP, ubiquitination assay, proteasome inhibitor experiments, rDNA transcription assay, in vitro and in vivo glioma models","journal":"Clinical cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic link shown by Co-IP and ubiquitination assay; single lab, single paper, novel substrate claim","pmids":["40627452"],"is_preprint":false},{"year":2021,"finding":"UBE2T mediates ubiquitination of BIRC5 (survivin) through interaction with DEPDC1B in chordoma cells; simultaneous downregulation of BIRC5 and DEPDC1B exacerbates the inhibitory effects, and BIRC5 overexpression reverses the inhibitory effects of DEPDC1B knockdown.","method":"Co-immunoprecipitation, RNA sequencing, ubiquitination assay, loss-of-function and rescue experiments in vitro and in vivo","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination shown but the direct UBE2T-BIRC5 enzymatic relationship is mediated through DEPDC1B; single lab","pmids":["34330893"],"is_preprint":false},{"year":2026,"finding":"Betulinic acid (BA) selectively suppresses UBE2T expression at the transcriptional level via MAPK/ERK pathway inhibition (pharmacological reactivation of ERK reverses UBE2T suppression), thereby blocking FANCL-UBE2T-mediated FANCI/FANCD2 monoubiquitination, impairing ICL repair, and sensitizing glioma to cisplatin.","method":"Western blot, RT-qPCR, mRNA stability assay, protein degradation assay, ERK reactivation rescue, in vivo xenograft, FANCD2 foci assay","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptional suppression via ERK shown by rescue experiment; single lab, no direct binding to UBE2T demonstrated","pmids":["41486508"],"is_preprint":false},{"year":2025,"finding":"UBE2T cooperates with E3 ligase TRIM28 to facilitate K48-linked ubiquitination and degradation of phospho-GSK3β (pGSK3β), disrupting the β-catenin destruction complex and promoting nuclear translocation of β-catenin, thereby activating prostate cancer stem cell self-renewal.","method":"Co-IP, in vivo ubiquitination assay (K48-linkage), IP-mass spectrometry, CETSA and SPR for β-elemene binding to UBE2T, xenograft models","journal":"Phytomedicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination assay for UBE2T/TRIM28/pGSK3β; single lab, novel substrate claim with partial mechanistic validation","pmids":["42070337"],"is_preprint":false},{"year":2024,"finding":"UBE2T mediates ubiquitination of the transcription factor PBX1, which then affects transcriptional regulation of RORA in lung adenocarcinoma; luciferase reporter assay, ChIP, and Co-IP established the UBE2T–PBX1–RORA regulatory axis.","method":"Co-immunoprecipitation, luciferase reporter assay, chromatin immunoprecipitation (ChIP), xenograft models","journal":"BMC cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and reporter assay for mechanism; single lab, single paper","pmids":["39289660"],"is_preprint":false},{"year":2024,"finding":"UBE2T mediates ubiquitination and degradation of SORBS3, thereby enhancing IL-6/STAT3 signaling and promoting lung adenocarcinoma progression; validated in vitro and in vivo.","method":"Co-immunoprecipitation, ubiquitination analysis, xenograft model, western blot","journal":"Journal of biochemical and molecular toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and ubiquitination assay; single lab","pmids":["38816989"],"is_preprint":false},{"year":2025,"finding":"UBE2T promotes papillary thyroid carcinoma progression by co-immunoprecipitating with SOCS2 and promoting its destabilization, thereby relieving SOCS2-mediated inhibition of STAT3 phosphorylation and activating JAK-STAT3 signaling.","method":"Co-immunoprecipitation, western blot, immunofluorescence, rescue experiments, in vitro invasion/migration assays","journal":"Seminars in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP; SOCS2 destabilization by UBE2T implied but direct ubiquitination not shown in abstract","pmids":["41330207"],"is_preprint":false}],"current_model":"UBE2T is the E2 ubiquitin-conjugating enzyme of the Fanconi anemia (FA) DNA repair pathway that physically binds the E3 ligase FANCL (via a structurally characterized specific interface) and catalyzes monoubiquitination of FANCD2 and FANCI on chromatin; this activity is stimulated by FANCI, restricted to correct lysine residues, regulated by DNA damage-induced chromatin recruitment of the E2/E3 holoenzyme independently of core complex assembly, and negatively autoregulated by UBE2T automonoubiquitination; UBE2T also participates in nucleotide excision repair, resolves transcription-replication conflicts and R-loops, and is subject to phosphorylation-dependent degradation by CaMKII-δ9 and to proteasomal degradation by the E3 ligase NEDD4L; beyond its canonical DNA repair role, UBE2T can ubiquitinate diverse substrates—including p53, RACK1, Akt, RPL6, HP1α, CDC42, CBX6, FOXO1, and others—often in an E3-independent or non-canonical manner to activate oncogenic signaling pathways (Wnt/β-catenin, PI3K/AKT, MAPK/ERK, JAK/STAT3) in multiple cancer types."},"narrative":{"mechanistic_narrative":"UBE2T is the dedicated E2 ubiquitin-conjugating enzyme of the Fanconi anemia (FA) DNA interstrand crosslink repair pathway, pairing with the E3 ligase FANCL to catalyze monoubiquitination of FANCD2 and FANCI on chromatin [PMID:16916645, PMID:19111657]. In vitro reconstitution established that FANCD2 monoubiquitination minimally requires UBE2T plus the FANCL RWD-like domain, with FANCI both stimulating the reaction and restricting it to the physiological substrate lysine K561, while FANCI itself is monoubiquitinated at K523 [PMID:19111657, PMID:19589784]. A crystal structure of the FANCL RING–UBE2T complex defined an extensive electrostatic and hydrophobic interface beyond the generic E2–E3 contact that determines selective recognition of UBE2T over other E2 enzymes [PMID:24389026]. This activity is governed by DNA damage-induced recruitment of UBE2T and FANCD2 to chromatin to form an active E2/E3 holoenzyme rather than by stable assembly of the core complex, and is negatively autoregulated by FANCL-stimulated UBE2T automonoubiquitination [PMID:16916645, PMID:17938197]. Biallelic loss-of-function mutations in UBE2T cause Fanconi anemia (FA-T subtype): patient cells lack FANCD2/FANCI monoubiquitination, fail to form FANCD2 foci, and are hypersensitive to crosslinkers, defects complemented by wild-type UBE2T [PMID:26119737, PMID:26046368, PMID:26085575]. Beyond crosslink repair, UBE2T contributes to nucleotide excision repair and to the resolution of R-loops and transcription-replication conflicts to maintain genome stability [PMID:22615860, PMID:36928776]. UBE2T protein abundance is controlled post-translationally by CaMKII-δ9-mediated phosphorylation-dependent degradation and by NEDD4L-directed proteasomal turnover [PMID:31481791, PMID:34838005]. In cancer, UBE2T acts as an oncogenic ubiquitin conjugator that ubiquitinates diverse substrates—including p53, RACK1, Akt, RPL6, CDC42, FOXO1, and CBX6—frequently through K48- or K63-linked chains and often independently of or in cooperation with various E3 ligases, thereby activating Wnt/β-catenin, PI3K/AKT, and related signaling outputs [PMID:33323973, PMID:35169125, PMID:36156329, PMID:39915000, PMID:39716485].","teleology":[{"year":2006,"claim":"Established UBE2T as the E2 enzyme essential for the Fanconi anemia pathway, answering which conjugating enzyme drives FANCD2 monoubiquitination and revealing a self-inactivation mechanism.","evidence":"Co-IP, in vivo ubiquitination, siRNA knockdown with chromosomal aberration readout, and autoubiquitination assays","pmids":["16916645"],"confidence":"High","gaps":["In vivo system did not define minimal biochemical requirements","Substrate lysine specificity not yet mapped"]},{"year":2007,"claim":"Showed that FA pathway E3 activity is gated by DNA damage-induced chromatin localization of an E2/E3 holoenzyme rather than by stable core-complex assembly, reframing how monoubiquitination is regulated.","evidence":"Chromatin fractionation and epistasis dissociating core complex assembly from E3 activity","pmids":["17938197"],"confidence":"High","gaps":["Molecular trigger of chromatin recruitment not defined","Does not identify the chromatin docking factor"]},{"year":2008,"claim":"Reconstituted FANCD2 monoubiquitination from purified components, defining the minimal UBE2T–FANCL requirement, the FANCL RWD domain role, and FANCI-dependent restriction to the K561 site.","evidence":"In vitro reconstitution with purified proteins, FANCL domain mutagenesis, addition of recombinant FANCI","pmids":["19111657"],"confidence":"High","gaps":["Structural basis of FANCI stimulation unresolved","Chromatin context absent from purified system"]},{"year":2009,"claim":"Identified FANCI K523 as the UBE2T–FANCL monoubiquitination site and defined FANCI's preference for branched DNA, extending the substrate repertoire of the pair.","evidence":"In vitro ubiquitination with purified UBE2T/FANCL and DNA binding assays on branched substrates","pmids":["19589784"],"confidence":"High","gaps":["Functional consequence of FANCI ubiquitination in repair not fully resolved","Single-lab biochemistry"]},{"year":2012,"claim":"Extended UBE2T function beyond crosslink repair to nucleotide excision repair, showing it promotes removal of UV photolesions.","evidence":"DT40 knockouts, UV sensitivity, genetic epistasis, photolesion removal assays","pmids":["22615860"],"confidence":"Medium","gaps":["Molecular mechanism linking UBE2T to NER not defined","Avian model; human relevance not directly tested"]},{"year":2014,"claim":"Provided the atomic basis for E2 selectivity, showing the FANCL RING–UBE2T interface uses specificity-determining contacts beyond the generic E2–E3 interaction.","evidence":"X-ray crystallography of FANCL RING–UBE2T with confirmatory mutagenesis","pmids":["24389026"],"confidence":"High","gaps":["Structure of full holoenzyme with substrate not resolved","Conformational dynamics during catalysis unaddressed"]},{"year":2015,"claim":"Demonstrated that biallelic UBE2T mutations cause Fanconi anemia (FA-T), causally linking the enzyme to human disease through patient cell complementation.","evidence":"Patient cell complementation, monoubiquitination western blots, FANCD2 foci imaging, crosslinker hypersensitivity, Co-IP for FANCL interaction","pmids":["26119737","26046368","26085575"],"confidence":"High","gaps":["Genotype–phenotype correlations across mutations incomplete","Non-DNA-repair contributions to disease not assessed"]},{"year":2019,"claim":"Defined post-translational control of UBE2T abundance through CaMKII-δ9 phosphorylation-driven degradation, linking loss of UBE2T-dependent repair to cardiomyopathy.","evidence":"Kinase assays, degradation assays, cardiac-specific mouse overexpression/knockout with DNA damage readouts","pmids":["31481791"],"confidence":"High","gaps":["Phosphosite-to-degradation E3 link not fully mapped","Generalizability beyond cardiomyocytes untested"]},{"year":2019,"claim":"Clarified that UBE2T loss only partially reduces homologous recombination, showing compensatory pathways operate in null cells.","evidence":"CRISPR knockout in HeLa/U2OS with fluorescent HR reporter quantification","pmids":["30715513"],"confidence":"Medium","gaps":["Identity of compensating pathways not defined","Negative/partial result; mechanism of compensation unknown"]},{"year":2020,"claim":"Began establishing an oncogenic, often E3-independent substrate repertoire for UBE2T, with RACK1 degradation activating Wnt/β-catenin in gastric cancer.","evidence":"Ubiquitination assays, RACK1 lysine mutagenesis, proteasome inhibition, Co-IP, small-molecule inhibitor studies","pmids":["33323973"],"confidence":"Medium","gaps":["E3-independence mechanism not structurally explained","Single-lineage context"]},{"year":2020,"claim":"Showed UBE2T can pair with alternative E3 ligases (RNF8) to monoubiquitinate γH2AX and drive CHK1 activation, expanding its damage-signaling roles beyond FANCL.","evidence":"Co-IP, chromatin fractionation, active-site (C86A) and substrate-site (K119/120R H2AX) mutagenesis, CHK1 phosphorylation assays","pmids":["33087136"],"confidence":"Medium","gaps":["Relative contribution versus canonical RNF8 E2s unclear","Single lab"]},{"year":2022,"claim":"Defined linkage-specific oncogenic conjugation, with UBE2T generating K63-linked Akt ubiquitination to activate Akt/β-catenin signaling and pyrimidine metabolism in HCC.","evidence":"Co-IP, K63-specific ubiquitination assay, C86A and K8/14R Akt mutagenesis, metabolomics, xenografts","pmids":["35169125"],"confidence":"Medium","gaps":["How UBE2T achieves K63 specificity without a defined E3 unresolved","Single lab"]},{"year":2023,"claim":"Connected UBE2T to replication-stress management in vivo, showing it resolves R-loops and stabilizes forks at transcription-replication conflicts in primordial germ cells.","evidence":"Ube2t knockout mice, R-loop and fork stability assays, DNA damage and p53 pathway readouts","pmids":["36928776"],"confidence":"Medium","gaps":["Direct molecular target at conflict sites not identified","Whether this requires FANCL pairing untested"]},{"year":2024,"claim":"Advanced UBE2T as a druggable enzyme by identifying multiple non-active-site binding pockets through fragment and NMR screening with structural validation.","evidence":"19F-NMR and HSQC fragment screening, X-ray co-crystal structures, in vitro activity inhibition; complementary fragment/zinc-induced plasticity studies","pmids":["38358126","28437106","28933844","31525021"],"confidence":"Medium","gaps":["Cellular potency and selectivity of leads not established","Pocket relevance to FA versus oncogenic functions unclear"]},{"year":2025,"claim":"Broadened the oncogenic substrate set to immune-evasion and stemness programs, with UBE2T degrading CDC42 and cooperating with TRIM-family E3s to degrade CBX6, relieving repression of stemness genes.","evidence":"Co-IP, GST pull-down, mass spectrometry, K48-linkage ubiquitination assays, site mutagenesis, flow cytometry, spontaneous tumor mouse models","pmids":["39915000","39716485"],"confidence":"Medium","gaps":["Direct versus indirect ubiquitination for some substrates not fully separated","Tissue specificity of substrate selection unexplained"]},{"year":null,"claim":"How a single E2 achieves its diverse, frequently E3-independent and linkage-specific oncogenic substrate selection while maintaining stringent FANCL-restricted FANCD2/FANCI monoubiquitination remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model for E3-independent substrate engagement","Determinants of K48 vs K63 vs monoubiquitination output unknown","Many cancer substrate claims rest on single Co-IP studies without reconstitution"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,13,16,22,26]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,6]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2,12]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,1,2,5,6,23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,13,16,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,13,16,26,27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,16,17,31]}],"complexes":["Fanconi anemia core complex (FANCL E2/E3 holoenzyme)"],"partners":["FANCL","FANCD2","FANCI","RNF8","NEDD4L","TRIM25","TRIM28","MULE"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NPD8","full_name":"Ubiquitin-conjugating enzyme E2 T","aliases":["Cell proliferation-inducing gene 50 protein","E2 ubiquitin-conjugating enzyme T","Ubiquitin carrier protein T","Ubiquitin-protein ligase T"],"length_aa":197,"mass_kda":22.5,"function":"Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. 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In vitro able to promote polyubiquitination using all 7 ubiquitin Lys residues, but may prefer 'Lys-11'-, 'Lys-27'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitination (PubMed:20061386)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NPD8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBE2T","classification":"Not Classified","n_dependent_lines":136,"n_total_lines":1208,"dependency_fraction":0.11258278145695365},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UBE2T","total_profiled":1310},"omim":[{"mim_id":"616435","title":"FANCONI ANEMIA, COMPLEMENTATION GROUP T; FANCT","url":"https://www.omim.org/entry/616435"},{"mim_id":"610538","title":"UBIQUITIN-CONJUGATING ENZYME E2 T; UBE2T","url":"https://www.omim.org/entry/610538"},{"mim_id":"227650","title":"FANCONI ANEMIA, COMPLEMENTATION GROUP A; FANCA","url":"https://www.omim.org/entry/227650"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid 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UBE2T also undergoes automonoubiquitination stimulated by FANCL, which inactivates UBE2T, providing a self-inactivation/negative regulatory mechanism.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assays, siRNA knockdown with chromosomal aberration readout, autoubiquitination assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo ubiquitination, loss-of-function phenotype; foundational paper replicated by multiple subsequent studies\",\n      \"pmids\": [\"16916645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In vitro reconstitution of FANCD2 monoubiquitination requires minimally UBE2T and FANCL. A conserved RWD-like domain in FANCL stimulates monoubiquitination. Addition of FANCI enhances monoubiquitination and restricts it to the in vivo substrate lysine residue on FANCD2 (K561).\",\n      \"method\": \"In vitro reconstitution of ubiquitination reaction with purified components; domain mutagenesis of FANCL; addition of recombinant FANCI\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro with purified proteins, mechanistic dissection of domain requirements, replicated in subsequent studies\",\n      \"pmids\": [\"19111657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UBE2T and FANCD2 are each recruited to chromatin independently of the FA core complex. The E3 ligase activity of the FA core complex is determined not by its stable assembly but by its DNA damage-induced localization to chromatin. Therefore, FANCD2 monoubiquitination is regulated by formation of an active E2/E3 holoenzyme on chromatin rather than by multiprotein complex assembly.\",\n      \"method\": \"Chromatin fractionation, cell biology epistasis experiments dissociating core complex assembly from E3 activity, subcellular localization studies\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — chromatin fractionation with functional dissection, multiple independent genetic dissections, replicated logic in subsequent studies\",\n      \"pmids\": [\"17938197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FANCI is monoubiquitinated on Lys-523 by the UBE2T–FANCL pair in vitro. FANCI and its C-terminal fragment possess a DNA binding activity that prefers branched DNA structures.\",\n      \"method\": \"In vitro ubiquitination assay with purified UBE2T and FANCL; DNA binding assay with branched DNA substrates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of FANCI monoubiquitination with site identification; single lab but orthogonal biochemical assays\",\n      \"pmids\": [\"19589784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of the FANCL RING domain in complex with UBE2T revealed a specific and extensive network of electrostatic and hydrophobic interactions beyond the generic E2–E3 interface that determines selective recognition of UBE2T over other E2 enzymes by FANCL.\",\n      \"method\": \"X-ray crystallography of FANCL RING–UBE2T complex; mutagenesis to confirm specificity-determining interactions\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution crystal structure with mutagenesis validation; single lab but rigorous structural method\",\n      \"pmids\": [\"24389026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"UBE2T (and FANCM) are required for nucleotide excision repair (NER) in addition to their role in ICL repair. UBE2T-deficient DT40 cells are unexpectedly sensitive to UV-induced DNA damage; genetic epistasis experiments indicate UBE2T collaborates to promote NER rather than translesion bypass, and UBE2T deficiency impairs efficient removal of UV-induced cyclobutane pyrimidine dimers.\",\n      \"method\": \"DT40 cell knockouts, UV sensitivity assays, genetic epistasis (double-mutant analysis), photolesion removal assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockouts with epistasis in avian model, photolesion removal assay; single lab\",\n      \"pmids\": [\"22615860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Biallelic loss-of-function mutations in UBE2T cause Fanconi anemia (FA-T subtype). Patient fibroblasts lack FANCD2 and FANCI monoubiquitination, fail to form FANCD2 foci after MMC treatment, and are hypersensitive to crosslinking agents; these defects are complemented by wild-type UBE2T expression. A missense mutation (p.Gln2Glu) abolishes FANCD2 monoubiquitination and FANCL interaction.\",\n      \"method\": \"Patient cell complementation assays, western blot for monoubiquitination, immunofluorescence for FANCD2 foci, crosslinker hypersensitivity assays, Co-IP for FANCL interaction\",\n      \"journal\": \"Cell reports / American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent patient cohorts, complementation assays, Co-IP, and functional readouts across three independent papers\",\n      \"pmids\": [\"26119737\", \"26046368\", \"26085575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CaMKII-δ9 phosphorylates UBE2T and targets it for degradation, thereby disrupting UBE2T-dependent DNA repair, causing accumulation of DNA damage and genome instability in cardiomyocytes, and promoting cardiomyopathy and heart failure.\",\n      \"method\": \"Kinase assay (CaMKII-δ9 phosphorylation of UBE2T), protein degradation assays, cardiac-specific overexpression and knockout mouse models, DNA damage readouts\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — kinase-substrate relationship demonstrated, in vivo mouse models with cardiac phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"31481791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Hypoxia rapidly and potently reduces UBE2T mRNA levels in cancer cell lines through reduced promoter activity (HIF-independent, not due to mRNA or protein stability changes), correlating with increased sensitivity to interstrand crosslinking agents and disruption of the FA pathway.\",\n      \"method\": \"Microarray, qPCR, western blot, HIF knockdown cell lines, RCC4 constitutive HIF1α cells, promoter activity assays, MMC survival assays\",\n      \"journal\": \"Radiotherapy and oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple gene expression methods plus promoter activity assay and HIF independence established; single lab\",\n      \"pmids\": [\"21722982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A novel allosteric binding pocket on UBE2T was identified through fragment screening; fragments binding to this site inhibit ubiquitin conjugation in vitro.\",\n      \"method\": \"Fragment screening by biophysical methods (SPR, DSF), in vitro ubiquitin conjugation inhibition assays\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with structural fragment binding; single lab, allosteric site confirmed biochemically\",\n      \"pmids\": [\"28437106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A zinc ion from a fragment library contaminant binds the active-site cysteine of UBE2T and induces a domain swap leading to cyclic trimerization in an open-ended linear assembly, revealing structural plasticity of the UBE2T active site.\",\n      \"method\": \"Co-crystal structure (X-ray crystallography), biophysical characterization (SPR/DSF), biochemical assays\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure with clear mechanistic insight; single study, single lab\",\n      \"pmids\": [\"28933844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A small-molecule inhibitor of UBE2T/FANCL-mediated FANCD2 monoubiquitylation was identified that sensitizes cells to the DNA cross-linking agent carboplatin, establishing UBE2T enzymatic activity as pharmacologically targetable.\",\n      \"method\": \"High-throughput screen-compatible in vitro ubiquitylation assay; cell sensitization to carboplatin\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay plus cellular phenotype; single lab, two orthogonal methods\",\n      \"pmids\": [\"31525021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UBE2T forms an E2–E3 pair with RNF8 and monoubiquitinates histone variant H2AX/γH2AX upon radiation exposure. This monoubiquitination facilitates CHK1 phosphorylation/activation and CHK1 release from chromatin to cytosol. E2-enzyme-deficient mutation C86A of UBE2T and monoubiquitination-site-deficient mutation K119/120R of H2AX both abrogate CHK1 activation.\",\n      \"method\": \"Co-immunoprecipitation (UBE2T–RNF8 E2–E3 pair), chromatin fractionation, immunofluorescence, active-site mutagenesis (C86A), substrate site mutagenesis (K119/120R H2AX), CHK1 phosphorylation assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for E2–E3 identification, active-site and substrate-site mutagenesis, chromatin fractionation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33087136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UBE2T promotes Wnt/β-catenin signaling hyperactivation in gastric cancer by mediating ubiquitination and proteasomal degradation of RACK1 at lysine residues K172, K225, and K257, independently of an E3 ligase.\",\n      \"method\": \"Ubiquitination assays, site-directed mutagenesis of RACK1 lysine residues, proteasome inhibitor experiments, Co-IP, small-molecule inhibitor (M435-1279) functional studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination site mapping by mutagenesis, E3-independent activity demonstrated biochemically; single lab, multiple methods\",\n      \"pmids\": [\"33323973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UBE2T promotes ubiquitination and degradation of FOXO1 in non-small cell lung cancer, activating Wnt/β-catenin signaling, and promoting EMT and radiation resistance.\",\n      \"method\": \"Co-immunoprecipitation, RNA-Seq, western blot, colony formation, flow cytometry, in vivo xenograft\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP for interaction, ubiquitination implied by protein level changes; mechanistic follow-up is partial in abstract\",\n      \"pmids\": [\"32590022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"UBE2T promotes ubiquitination and degradation of p53, decreasing p53, p21, and Noxa levels, thereby facilitating hepatocellular carcinoma cell growth.\",\n      \"method\": \"Western blot, ectopic overexpression and knockdown, ubiquitination assay of p53\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, ubiquitination assay of p53 shown but limited mechanistic detail in abstract; replicated in other cancer contexts\",\n      \"pmids\": [\"28935368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UBE2T promotes K63-linked ubiquitination of Akt, activating Akt/β-catenin signaling; E2-enzyme-deficient mutation C86A of UBE2T and ubiquitination-site-deficient mutation K8/14R of Akt impair downstream pathway activation and pyrimidine enzyme upregulation in HCC.\",\n      \"method\": \"Co-immunoprecipitation, K63-specific ubiquitination assay, active-site mutagenesis (C86A UBE2T), substrate mutagenesis (K8/14R Akt), LC/MS-MS metabolomics, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — active-site and substrate-site mutagenesis with functional readout, K63 linkage specificity established; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35169125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UBE2T physically binds the E3 ubiquitin ligase Mule and regulates its protein level via ubiquitination, thereby preventing Mule-mediated degradation of β-catenin and promoting liver CSC functions. This effect requires the E2 catalytic activity of UBE2T.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, E2-activity-impaired mutant, β-catenin degradation assays, sphere formation and tumorigenicity assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct binding, ubiquitination assay, E2 activity mutant confirmation; single lab, multiple methods\",\n      \"pmids\": [\"33542213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NEDD4L is an E3 ligase that ubiquitinates UBE2T and targets it for proteasomal degradation, reducing UBE2T protein half-life; NEDD4L-mediated UBE2T degradation represses PI3K-AKT signaling and suppresses lung adenocarcinoma cell progression.\",\n      \"method\": \"Half-life analysis, in vivo ubiquitylation assay, NEDD4L overexpression/depletion, Co-IP, xenograft models\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — E3 ubiquitin ligase-substrate relationship with half-life and in vivo ubiquitination assay; single lab, multiple methods\",\n      \"pmids\": [\"34838005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SENP1 deSUMOylates UBE2T, increasing UBE2T protein expression and activating the Akt pathway, promoting HCC progression. UBE2T is thus identified as a SUMOylation substrate regulated by SENP1.\",\n      \"method\": \"SENP1 knockout model, Co-IP, deSUMOylation assay, western blot, in vitro and in vivo tumor assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and deSUMOylation assay shown; single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"31969492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBE2T catalyzes RING1-mediated ubiquitination of p53, relieving transcriptional repression of ribonucleotide reductase subunits RRM1 and RRM2, resulting in unrestrained pyrimidine biosynthesis and alleviation of replication stress in pancreatic cancer, conferring gemcitabine resistance.\",\n      \"method\": \"Spontaneous KPC Ube2t-conditional knockout mice, organoids, PDX, proteomics, metabolomics, transcriptional reporter assays\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional knockout with survival benefit, combined proteomics and metabolomics; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36842710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UBE2T directly binds FANCI and regulates its monoubiquitination; overexpression of UBE2T reversed effects of FANCI knockdown in NSCLC cells, placing UBE2T upstream of FANCI monoubiquitination in a cancer context.\",\n      \"method\": \"Co-immunoprecipitation confirming UBE2T–FANCI direct binding, monoubiquitination assay, rescue experiments\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with partial follow-up; single lab\",\n      \"pmids\": [\"35703356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UBE2T mediates K48-linked polyubiquitination and degradation of ribosomal protein L6 (RPL6) in an E3 ligase-independent manner in glioblastoma, reducing wild-type p53 and enhancing gain-of-function mutant p53.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with K48 linkage specificity, in vitro and in vivo GBM models\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, K48 linkage demonstrated but E3-independence claim has limited mechanistic validation in abstract\",\n      \"pmids\": [\"36156329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBE2T resolves R-loops and stabilizes replication forks at transcription-replication conflict sites and common fragile sites in primordial germ cells (PGCs), and promotes mitotic DNA synthesis to maintain genome stability; Ube2t knockout mice show defects in PGC proliferation with DNA damage accumulation and p53 pathway activation.\",\n      \"method\": \"Ube2t knockout mice, R-loop detection assays, replication fork stability assays, DNA damage markers, p53 pathway activation readouts\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout with multiple mechanistic readouts; single lab, clean genetic model with multiple cellular phenotypes\",\n      \"pmids\": [\"36928776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CRISPR/Cas9-mediated knockout of UBE2T in HeLa and U2OS cells only partially reduced homologous recombination (HR), demonstrating that UBE2T-independent pathways can compensate for the recombination defect in UBE2T/FANCT null cells.\",\n      \"method\": \"CRISPR/Cas9 knockout, fluorescent reporter recombination assay, HR quantification\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean CRISPR knockout with quantitative HR reporter assay; negative/partial result rigorously established in single lab\",\n      \"pmids\": [\"30715513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Fragment screening by 19F-NMR and 1H-15N-HSQC, validated by X-ray crystallography, identified two new binding pockets on UBE2T distinct from the active site; compounds binding these sites show inhibitory activity on UBE2T ubiquitination.\",\n      \"method\": \"19F-NMR fragment screening, 1H-15N-HSQC NMR validation, X-ray co-crystal structures, in vitro UBE2T activity assays\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR and X-ray structure with functional inhibition assay; single lab, multiple orthogonal biophysical methods\",\n      \"pmids\": [\"38358126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UBE2T mediates K48-linked polyubiquitination and proteasomal degradation of CDC42, thereby preventing CDC42-mediated autophagic lysosomal degradation of CD276 (B7-H3), leading to CD276 upregulation, impairment of CD8+ T cell function, and immune escape in triple-negative breast cancer.\",\n      \"method\": \"Co-IP, GST pull-down, mass spectrometry, western blot, ubiquitination assay (K48-linkage), flow cytometry, immunofluorescence, in vivo models\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and GST pulldown for direct interaction, K48 linkage specificity, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"39915000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBE2T collaborates with E3 ligase TRIM25 to perform K48-linked polyubiquitination and degradation of CBX6 at K214, relieving transcriptional repression of pluripotency genes SOX2 and NANOG and enhancing breast cancer stem cell stemness.\",\n      \"method\": \"Co-IP, in vivo ubiquitination assay (K48-specific), site mutagenesis (K214R CBX6), spontaneous MMTV-PyMT mouse model, organoids, scRNA-seq\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination with linkage and site specificity, in vivo genetic model; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39716485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UBE2T mediates ubiquitination-dependent degradation of HP1α via the proteasome pathway in IDH1/TP53-mutant glioma, leading to release of suppressive effects of R-2-hydroxyglutarate on nucleolar function and increased rDNA transcription.\",\n      \"method\": \"Co-IP, ubiquitination assay, proteasome inhibitor experiments, rDNA transcription assay, in vitro and in vivo glioma models\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic link shown by Co-IP and ubiquitination assay; single lab, single paper, novel substrate claim\",\n      \"pmids\": [\"40627452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UBE2T mediates ubiquitination of BIRC5 (survivin) through interaction with DEPDC1B in chordoma cells; simultaneous downregulation of BIRC5 and DEPDC1B exacerbates the inhibitory effects, and BIRC5 overexpression reverses the inhibitory effects of DEPDC1B knockdown.\",\n      \"method\": \"Co-immunoprecipitation, RNA sequencing, ubiquitination assay, loss-of-function and rescue experiments in vitro and in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination shown but the direct UBE2T-BIRC5 enzymatic relationship is mediated through DEPDC1B; single lab\",\n      \"pmids\": [\"34330893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Betulinic acid (BA) selectively suppresses UBE2T expression at the transcriptional level via MAPK/ERK pathway inhibition (pharmacological reactivation of ERK reverses UBE2T suppression), thereby blocking FANCL-UBE2T-mediated FANCI/FANCD2 monoubiquitination, impairing ICL repair, and sensitizing glioma to cisplatin.\",\n      \"method\": \"Western blot, RT-qPCR, mRNA stability assay, protein degradation assay, ERK reactivation rescue, in vivo xenograft, FANCD2 foci assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptional suppression via ERK shown by rescue experiment; single lab, no direct binding to UBE2T demonstrated\",\n      \"pmids\": [\"41486508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UBE2T cooperates with E3 ligase TRIM28 to facilitate K48-linked ubiquitination and degradation of phospho-GSK3β (pGSK3β), disrupting the β-catenin destruction complex and promoting nuclear translocation of β-catenin, thereby activating prostate cancer stem cell self-renewal.\",\n      \"method\": \"Co-IP, in vivo ubiquitination assay (K48-linkage), IP-mass spectrometry, CETSA and SPR for β-elemene binding to UBE2T, xenograft models\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination assay for UBE2T/TRIM28/pGSK3β; single lab, novel substrate claim with partial mechanistic validation\",\n      \"pmids\": [\"42070337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBE2T mediates ubiquitination of the transcription factor PBX1, which then affects transcriptional regulation of RORA in lung adenocarcinoma; luciferase reporter assay, ChIP, and Co-IP established the UBE2T–PBX1–RORA regulatory axis.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay, chromatin immunoprecipitation (ChIP), xenograft models\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and reporter assay for mechanism; single lab, single paper\",\n      \"pmids\": [\"39289660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBE2T mediates ubiquitination and degradation of SORBS3, thereby enhancing IL-6/STAT3 signaling and promoting lung adenocarcinoma progression; validated in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination analysis, xenograft model, western blot\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and ubiquitination assay; single lab\",\n      \"pmids\": [\"38816989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UBE2T promotes papillary thyroid carcinoma progression by co-immunoprecipitating with SOCS2 and promoting its destabilization, thereby relieving SOCS2-mediated inhibition of STAT3 phosphorylation and activating JAK-STAT3 signaling.\",\n      \"method\": \"Co-immunoprecipitation, western blot, immunofluorescence, rescue experiments, in vitro invasion/migration assays\",\n      \"journal\": \"Seminars in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP; SOCS2 destabilization by UBE2T implied but direct ubiquitination not shown in abstract\",\n      \"pmids\": [\"41330207\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBE2T is the E2 ubiquitin-conjugating enzyme of the Fanconi anemia (FA) DNA repair pathway that physically binds the E3 ligase FANCL (via a structurally characterized specific interface) and catalyzes monoubiquitination of FANCD2 and FANCI on chromatin; this activity is stimulated by FANCI, restricted to correct lysine residues, regulated by DNA damage-induced chromatin recruitment of the E2/E3 holoenzyme independently of core complex assembly, and negatively autoregulated by UBE2T automonoubiquitination; UBE2T also participates in nucleotide excision repair, resolves transcription-replication conflicts and R-loops, and is subject to phosphorylation-dependent degradation by CaMKII-δ9 and to proteasomal degradation by the E3 ligase NEDD4L; beyond its canonical DNA repair role, UBE2T can ubiquitinate diverse substrates—including p53, RACK1, Akt, RPL6, HP1α, CDC42, CBX6, FOXO1, and others—often in an E3-independent or non-canonical manner to activate oncogenic signaling pathways (Wnt/β-catenin, PI3K/AKT, MAPK/ERK, JAK/STAT3) in multiple cancer types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBE2T is the dedicated E2 ubiquitin-conjugating enzyme of the Fanconi anemia (FA) DNA interstrand crosslink repair pathway, pairing with the E3 ligase FANCL to catalyze monoubiquitination of FANCD2 and FANCI on chromatin [#0, #1]. In vitro reconstitution established that FANCD2 monoubiquitination minimally requires UBE2T plus the FANCL RWD-like domain, with FANCI both stimulating the reaction and restricting it to the physiological substrate lysine K561, while FANCI itself is monoubiquitinated at K523 [#1, #3]. A crystal structure of the FANCL RING–UBE2T complex defined an extensive electrostatic and hydrophobic interface beyond the generic E2–E3 contact that determines selective recognition of UBE2T over other E2 enzymes [#4]. This activity is governed by DNA damage-induced recruitment of UBE2T and FANCD2 to chromatin to form an active E2/E3 holoenzyme rather than by stable assembly of the core complex, and is negatively autoregulated by FANCL-stimulated UBE2T automonoubiquitination [#0, #2]. Biallelic loss-of-function mutations in UBE2T cause Fanconi anemia (FA-T subtype): patient cells lack FANCD2/FANCI monoubiquitination, fail to form FANCD2 foci, and are hypersensitive to crosslinkers, defects complemented by wild-type UBE2T [#6]. Beyond crosslink repair, UBE2T contributes to nucleotide excision repair and to the resolution of R-loops and transcription-replication conflicts to maintain genome stability [#5, #23]. UBE2T protein abundance is controlled post-translationally by CaMKII-δ9-mediated phosphorylation-dependent degradation and by NEDD4L-directed proteasomal turnover [#7, #18]. In cancer, UBE2T acts as an oncogenic ubiquitin conjugator that ubiquitinates diverse substrates—including p53, RACK1, Akt, RPL6, CDC42, FOXO1, and CBX6—frequently through K48- or K63-linked chains and often independently of or in cooperation with various E3 ligases, thereby activating Wnt/β-catenin, PI3K/AKT, and related signaling outputs [#13, #16, #22, #26, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established UBE2T as the E2 enzyme essential for the Fanconi anemia pathway, answering which conjugating enzyme drives FANCD2 monoubiquitination and revealing a self-inactivation mechanism.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitination, siRNA knockdown with chromosomal aberration readout, and autoubiquitination assays\",\n      \"pmids\": [\"16916645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo system did not define minimal biochemical requirements\", \"Substrate lysine specificity not yet mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that FA pathway E3 activity is gated by DNA damage-induced chromatin localization of an E2/E3 holoenzyme rather than by stable core-complex assembly, reframing how monoubiquitination is regulated.\",\n      \"evidence\": \"Chromatin fractionation and epistasis dissociating core complex assembly from E3 activity\",\n      \"pmids\": [\"17938197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger of chromatin recruitment not defined\", \"Does not identify the chromatin docking factor\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Reconstituted FANCD2 monoubiquitination from purified components, defining the minimal UBE2T–FANCL requirement, the FANCL RWD domain role, and FANCI-dependent restriction to the K561 site.\",\n      \"evidence\": \"In vitro reconstitution with purified proteins, FANCL domain mutagenesis, addition of recombinant FANCI\",\n      \"pmids\": [\"19111657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FANCI stimulation unresolved\", \"Chromatin context absent from purified system\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified FANCI K523 as the UBE2T–FANCL monoubiquitination site and defined FANCI's preference for branched DNA, extending the substrate repertoire of the pair.\",\n      \"evidence\": \"In vitro ubiquitination with purified UBE2T/FANCL and DNA binding assays on branched substrates\",\n      \"pmids\": [\"19589784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of FANCI ubiquitination in repair not fully resolved\", \"Single-lab biochemistry\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended UBE2T function beyond crosslink repair to nucleotide excision repair, showing it promotes removal of UV photolesions.\",\n      \"evidence\": \"DT40 knockouts, UV sensitivity, genetic epistasis, photolesion removal assays\",\n      \"pmids\": [\"22615860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking UBE2T to NER not defined\", \"Avian model; human relevance not directly tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided the atomic basis for E2 selectivity, showing the FANCL RING–UBE2T interface uses specificity-determining contacts beyond the generic E2–E3 interaction.\",\n      \"evidence\": \"X-ray crystallography of FANCL RING–UBE2T with confirmatory mutagenesis\",\n      \"pmids\": [\"24389026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full holoenzyme with substrate not resolved\", \"Conformational dynamics during catalysis unaddressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that biallelic UBE2T mutations cause Fanconi anemia (FA-T), causally linking the enzyme to human disease through patient cell complementation.\",\n      \"evidence\": \"Patient cell complementation, monoubiquitination western blots, FANCD2 foci imaging, crosslinker hypersensitivity, Co-IP for FANCL interaction\",\n      \"pmids\": [\"26119737\", \"26046368\", \"26085575\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype–phenotype correlations across mutations incomplete\", \"Non-DNA-repair contributions to disease not assessed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined post-translational control of UBE2T abundance through CaMKII-δ9 phosphorylation-driven degradation, linking loss of UBE2T-dependent repair to cardiomyopathy.\",\n      \"evidence\": \"Kinase assays, degradation assays, cardiac-specific mouse overexpression/knockout with DNA damage readouts\",\n      \"pmids\": [\"31481791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosite-to-degradation E3 link not fully mapped\", \"Generalizability beyond cardiomyocytes untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Clarified that UBE2T loss only partially reduces homologous recombination, showing compensatory pathways operate in null cells.\",\n      \"evidence\": \"CRISPR knockout in HeLa/U2OS with fluorescent HR reporter quantification\",\n      \"pmids\": [\"30715513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of compensating pathways not defined\", \"Negative/partial result; mechanism of compensation unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Began establishing an oncogenic, often E3-independent substrate repertoire for UBE2T, with RACK1 degradation activating Wnt/β-catenin in gastric cancer.\",\n      \"evidence\": \"Ubiquitination assays, RACK1 lysine mutagenesis, proteasome inhibition, Co-IP, small-molecule inhibitor studies\",\n      \"pmids\": [\"33323973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3-independence mechanism not structurally explained\", \"Single-lineage context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed UBE2T can pair with alternative E3 ligases (RNF8) to monoubiquitinate γH2AX and drive CHK1 activation, expanding its damage-signaling roles beyond FANCL.\",\n      \"evidence\": \"Co-IP, chromatin fractionation, active-site (C86A) and substrate-site (K119/120R H2AX) mutagenesis, CHK1 phosphorylation assays\",\n      \"pmids\": [\"33087136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution versus canonical RNF8 E2s unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined linkage-specific oncogenic conjugation, with UBE2T generating K63-linked Akt ubiquitination to activate Akt/β-catenin signaling and pyrimidine metabolism in HCC.\",\n      \"evidence\": \"Co-IP, K63-specific ubiquitination assay, C86A and K8/14R Akt mutagenesis, metabolomics, xenografts\",\n      \"pmids\": [\"35169125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How UBE2T achieves K63 specificity without a defined E3 unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected UBE2T to replication-stress management in vivo, showing it resolves R-loops and stabilizes forks at transcription-replication conflicts in primordial germ cells.\",\n      \"evidence\": \"Ube2t knockout mice, R-loop and fork stability assays, DNA damage and p53 pathway readouts\",\n      \"pmids\": [\"36928776\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target at conflict sites not identified\", \"Whether this requires FANCL pairing untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Advanced UBE2T as a druggable enzyme by identifying multiple non-active-site binding pockets through fragment and NMR screening with structural validation.\",\n      \"evidence\": \"19F-NMR and HSQC fragment screening, X-ray co-crystal structures, in vitro activity inhibition; complementary fragment/zinc-induced plasticity studies\",\n      \"pmids\": [\"38358126\", \"28437106\", \"28933844\", \"31525021\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular potency and selectivity of leads not established\", \"Pocket relevance to FA versus oncogenic functions unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened the oncogenic substrate set to immune-evasion and stemness programs, with UBE2T degrading CDC42 and cooperating with TRIM-family E3s to degrade CBX6, relieving repression of stemness genes.\",\n      \"evidence\": \"Co-IP, GST pull-down, mass spectrometry, K48-linkage ubiquitination assays, site mutagenesis, flow cytometry, spontaneous tumor mouse models\",\n      \"pmids\": [\"39915000\", \"39716485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect ubiquitination for some substrates not fully separated\", \"Tissue specificity of substrate selection unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single E2 achieves its diverse, frequently E3-independent and linkage-specific oncogenic substrate selection while maintaining stringent FANCL-restricted FANCD2/FANCI monoubiquitination remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model for E3-independent substrate engagement\", \"Determinants of K48 vs K63 vs monoubiquitination output unknown\", \"Many cancer substrate claims rest on single Co-IP studies without reconstitution\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 13, 16, 22, 26]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 12]},\n      {\"term_id\": \"GO:0061659\", \"supporting_discovery_ids\": []}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 13, 16, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 13, 16, 26, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 16, 17, 31]}\n    ],\n    \"complexes\": [\"Fanconi anemia core complex (FANCL E2/E3 holoenzyme)\"],\n    \"partners\": [\"FANCL\", \"FANCD2\", \"FANCI\", \"RNF8\", \"NEDD4L\", \"TRIM25\", \"TRIM28\", \"Mule\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}