UBE2T (ubiquitin-conjugating enzyme E2 T; also PIG50/HSPC150) is the E2 ubiquitin-conjugating enzyme of the Fanconi anemia (FA) DNA interstrand cross-link repair pathway. It is a 197-residue member of the UBC family with a canonical ubiquitin-conjugating catalytic core and active-site Cys86 that forms the ubiquitin thioester intermediate. UBE2T pairs specifically and exclusively with the RING E3 ubiquitin ligase FANCL of the FA core complex, and this cognate E2/E3 holoenzyme catalyzes the site-specific monoubiquitination of FANCD2 (and of FANCI) — the central activating step of the FA pathway that promotes recruitment of downstream DNA repair factors to interstrand cross-links and stalled replication forks. FANCL selectivity for UBE2T is achieved through an extensive electrostatic/hydrogen-bond network beyond the generic hydrophobic E2/E3 interface, with Arg60 of UBE2T acting as the key positive selector. Regulation of FANCD2 monoubiquitination occurs by DNA-damage-induced localization of the enzymes to chromatin rather than by assembly of the core complex; UBE2T is constitutively present in the nuclear/chromatin compartment. UBE2T also undergoes self-limiting automonoubiquitination (Lys-91/Lys-182) that has been reported to down-regulate its activity. Biallelic loss-of-function of UBE2T causes Fanconi anemia (complementation group FANCT/FA-T), a chromosomal-instability disorder with bone marrow failure, developmental malformations, and cancer predisposition. Additional activities reported outside the canonical pathway — polyubiquitination and downregulation of BRCA1 in overexpressing breast-cancer cells, and an intrinsic in-vitro ability (in the absence of an E3) to build polyubiquitin chains through several ubiquitin lysines — are context-specific or non-physiological.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000209 protein polyubiquitination | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) annotation to protein polyubiquitination, a family-level capability of UBC E2s. UBE2T can drive polyubiquitination in vitro and polyubiquitinates BRCA1 in overexpression settings, but its physiological FA role is monoubiquitination of FANCD2/FANCI. Reason: Not incorrect — UBE2T has demonstrable polyubiquitination capacity (PMID:20061386, PMID:19887602) — but polyubiquitination is not the core biological function of UBE2T, which is site-specific monoubiquitination in the FA pathway. Retained as a valid non-core annotation. Supporting Evidence: PMID:19887602 BRCA1 to be polyubiquitinated by incubation with |
| GO:0061631 ubiquitin conjugating enzyme activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to the core E2 ubiquitin-conjugating enzyme activity. This is the defining molecular function of UBE2T. Reason: Well supported at both the family (IBA) and gene-specific experimental levels. UBE2T is the E2 essential for the FA pathway, accepting ubiquitin from E1 and, with FANCL, transferring it to FANCD2/FANCI. This is the correctly specific MF term for an E2 and represents the core function. Supporting Evidence: PMID:16916645 UBE2T is the ubiquitin-conjugating enzyme (E2) essential for this pathway. |
| GO:0006974 DNA damage response | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation placing UBE2T in the DNA damage response, consistent with its role in the FA pathway triggered by replication-blocking DNA lesions. Reason: Consistent with experimental evidence: UBE2T-catalyzed FANCD2 monoubiquitination is a DNA-damage/S-phase-restricted event and UBE2T depletion produces the DNA-damage-associated chromosomal abnormalities of FA. Supporting Evidence: PMID:17938197 The Fanconi anemia (FA) nuclear core complex and the E2 ubiquitin-conjugating enzyme UBE2T are required for the S phase and DNA damage-restricted monoubiquitination of FANCD2. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation (from UniProt subcellular-location mapping) to nucleus, matching the UniProt SUBCELLULAR LOCATION and experimental data. Reason: UBE2T is a nuclear protein that accumulates on chromatin; the nuclear location is experimentally established and is where UBE2T functions in the FA pathway. Supporting Evidence: PMID:17938197 UBE2T and FANCD2 access this subcellular fraction independently of the FA core complex. |
| GO:0019787 ubiquitin-like protein transferase activity | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic (ARBA) annotation to a broad parent molecular-function term encompassing ubiquitin/UBL transfer. Reason: Correct but less specific than the E2-specific GO:0061631 that is also annotated. A broader electronic term is acceptable; no change needed, though it is not the most informative representation of UBE2T's activity. |
| GO:0032446 protein modification by small protein conjugation | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic (ARBA) annotation to a broad parent process for ubiquitin/UBL conjugation. Reason: A correct high-level process term consistent with UBE2T's ubiquitin-conjugating role. Broader than the specific monoubiquitination/ICL-repair processes but not wrong; acceptable as a general electronic annotation. |
| GO:0061631 ubiquitin conjugating enzyme activity | IEA GO_REF:0000003 | ACCEPT | Summary: Electronic annotation from EC 2.3.2.23 mapping to E2 ubiquitin-conjugating enzyme activity — the core molecular function of UBE2T. Reason: EC 2.3.2.23 is assigned to UBE2T with experimental support (PMID:20061386) and maps correctly to the E2 activity term, which is also supported experimentally and phylogenetically. Core function. |
| GO:0005515 protein binding | IPI PMID:24389026 Structure of the human FANCL RING-Ube2T complex reveals dete... | KEEP AS NON CORE | Summary: IPI protein-binding annotation from the FANCL RING–UBE2T structure (interactor FANCL, Q9NW38). This physical interaction is central to UBE2T function but is captured uninformatively here. Reason: The FANCL interaction is real and important, but 'protein binding' (GO:0005515) is uninformative; the same interaction is better represented by the ubiquitin-protein-ligase-binding annotations (GO:0031625). Retained as valid but non-core; the informative term is preferred for core representation. Supporting Evidence: PMID:24389026 FANCL exclusively formed a complex with Ube2T |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: IPI protein-binding annotation to GNB2 (P62879) from a large-scale neurodegenerative-disease yeast two-hybrid interactome. Reason: A high-throughput binary interaction of unclear biological significance for UBE2T's function; also recorded in UniProt INTERACTION. Generic 'protein binding' is uninformative. Retained as non-core rather than removed, since the interaction is documented. |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | ACCEPT | Summary: Electronic annotation (UniPathway mapping) to the general protein ubiquitination process. Reason: A correct broad process term for an E2 ubiquitin-conjugating enzyme. Broader than the specific monoubiquitination role but accurate; acceptable as a general electronic annotation. |
| GO:0005634 nucleus | EXP PMID:19887602 Ubiquitination and downregulation of BRCA1 by ubiquitin-conj... | ACCEPT | Summary: Experimental nuclear localization of UBE2T in breast cancer cells. Reason: Direct experimental support for the nuclear localization that is consistent with UBE2T's function; matches UniProt SUBCELLULAR LOCATION 'Nucleus'. Supporting Evidence: PMID:19887602 UBE2T interacted and colocalized with the BRCA1/BRCA1-associated RING domain protein (BARD1) complex. |
| GO:0061631 ubiquitin conjugating enzyme activity | EXP PMID:20061386 The E2 ubiquitin-conjugating enzymes direct polyubiquitinati... | ACCEPT | Summary: Experimental demonstration of UBE2T E2 ubiquitin-conjugating enzyme activity (catalytic activity underlying EC 2.3.2.23). Reason: David et al. purified and assayed UBE2T among all human E2s, confirming its E2 conjugating activity. Core molecular function. Supporting Evidence: PMID:20061386 the E2 enzymes are capable of directing the ubiquitination process to distinct subsets of ubiquitin lysines, depending on the specific E2 utilized |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8852130 | ACCEPT | Summary: Reactome (TAS) nucleoplasm location, from the reaction in which E1 (UBA1) charges nuclear E2 enzymes with ubiquitin. Reason: Nucleoplasm is a valid, appropriately specific nuclear location for UBE2T, consistent with its nuclear/chromatin localization and its function there in the FA pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785361 | ACCEPT | Summary: Reactome (TAS) nucleoplasm location, from the FANCD2:FANCI monoubiquitination reaction of the FA pathway. Reason: Consistent with UBE2T functioning in the nucleus/on chromatin during FANCD2/FANCI monoubiquitination. Valid location annotation. |
| GO:0061631 ubiquitin conjugating enzyme activity | IDA PMID:19589784 FANCI binds branched DNA and is monoubiquitinated by UBE2T-F... | ACCEPT | Summary: Direct assay (IDA) of UBE2T E2 activity: the UBE2T-FANCL pair monoubiquitinates FANCI on Lys-523 in vitro. Reason: Direct experimental support for UBE2T's E2 conjugating enzyme activity in the FA pathway context. Core molecular function. Supporting Evidence: PMID:19589784 FANCI can be ubiquitinated on Lys-523 by the UBE2T-FANCL pair in vitro |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785342 | ACCEPT | Summary: Reactome (TAS) nucleoplasm location, from the reaction in which the FANCD2:FANCI complex and UBE2T bind ICL-DNA associated with the FA core complex. Reason: Valid nuclear location consistent with UBE2T acting at ICL-DNA/chromatin within the FA pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6788385 | ACCEPT | Summary: Reactome (TAS) nucleoplasm location, associated with FA-pathway reactions at ICL-DNA. Reason: Valid, appropriately specific nuclear location for UBE2T consistent with its site of action. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6788392 | ACCEPT | Summary: Reactome (TAS) nucleoplasm location, associated with FA-pathway reactions at ICL-DNA. Reason: Valid nuclear location consistent with UBE2T's nuclear/chromatin function in the FA pathway. |
| GO:0003682 chromatin binding | IDA PMID:17938197 UBE2T, the Fanconi anemia core complex, and FANCD2 are recru... | KEEP AS NON CORE | Summary: IDA chromatin-binding annotation reflecting UBE2T's constitutive presence in and accumulation on the chromatin fraction, where it forms the active E2/E3 holoenzyme with FANCL. Reason: Experimentally supported chromatin association (UBE2T is constitutively present in the chromatin compartment and FANCD2 monoubiquitination is regulated by localization to chromatin). This localization/binding supports but is not itself the core catalytic function; retained as non-core. Supporting Evidence: PMID:17938197 The E2-conjugating enzyme UBE2T is constitutively present in this compartment. |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:16916645 UBE2T is the E2 in the Fanconi anemia pathway and undergoes ... | MODIFY | Summary: IDA annotation to the general ubiquitin-protein transferase activity term based on UBE2T's demonstrated role as the E2 that transfers ubiquitin to FANCD2. Reason: Correct in essence but not the most specific/informative term. UBE2T is an E2 ubiquitin-conjugating enzyme; the E2-specific molecular function GO:0061631 (ubiquitin conjugating enzyme activity) better represents its activity than the broader GO:0004842 (which also covers E3 ligase activity). Proposed replacements: ubiquitin conjugating enzyme activity Supporting Evidence: PMID:16916645 UBE2T is the ubiquitin-conjugating enzyme (E2) essential for this pathway. |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:17938197 UBE2T, the Fanconi anemia core complex, and FANCD2 are recru... | MODIFY | Summary: IDA annotation to the general ubiquitin-protein transferase activity term from the reconstituted FANCD2 monoubiquitination system. Reason: As above, the E2-specific term GO:0061631 is the more accurate/informative molecular function for UBE2T than the broader GO:0004842. Proposed replacements: ubiquitin conjugating enzyme activity Supporting Evidence: PMID:17938197 the E2 ubiquitin-conjugating enzyme UBE2T are required for the S phase and DNA damage-restricted monoubiquitination of FANCD2 |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:19111657 Mechanistic insight into site-restricted monoubiquitination ... | MODIFY | Summary: IDA annotation to general ubiquitin-protein transferase activity from the minimal Ube2t/FANCL FANCD2 monoubiquitination reconstitution. Reason: Essence is correct but the E2-specific GO:0061631 is the more precise molecular function term for UBE2T. Proposed replacements: ubiquitin conjugating enzyme activity Supporting Evidence: PMID:19111657 we minimally reconstitute this monoubiquitination reaction with Ube2t and the FANCL protein |
| GO:0005634 nucleus | TAS PMID:17938197 UBE2T, the Fanconi anemia core complex, and FANCD2 are recru... | ACCEPT | Summary: TAS nuclear localization annotation, consistent with experimental and UniProt-curated nuclear localization. Reason: UBE2T is nuclear and functions there in the FA pathway; the nuclear location is well established. Supporting Evidence: PMID:17938197 UBE2T and FANCD2 access this subcellular fraction independently of the FA core complex. |
| GO:0006281 DNA repair | IMP PMID:16916645 UBE2T is the E2 in the Fanconi anemia pathway and undergoes ... | MODIFY | Summary: IMP annotation to DNA repair: UBE2T depletion impairs mitomycin-C-induced repair and produces the chromosomal abnormalities characteristic of FA. Reason: Correct but too general. UBE2T's function is specifically in the Fanconi anemia DNA interstrand cross-link (ICL) repair pathway (the IMP evidence uses mitomycin C, an ICL-inducing agent). The more specific process term GO:0036297 (interstrand cross-link repair) better represents this role. Proposed replacements: interstrand cross-link repair Supporting Evidence: PMID:16916645 DNA damage in UBE2T-depleted cells leads to the formation of abnormal chromosomes that are a hallmark of Fanconi anemia. |
| GO:0006513 protein monoubiquitination | IDA PMID:16916645 UBE2T is the E2 in the Fanconi anemia pathway and undergoes ... | ACCEPT | Summary: IDA annotation to protein monoubiquitination — the central FA-pathway activity of UBE2T (monoubiquitination of FANCD2, required in vivo). Reason: Directly supported and represents the core biological process catalyzed by UBE2T with FANCL: site-specific monoubiquitination of FANCD2. Supporting Evidence: PMID:16916645 is required for the monoubiquitination of FANCD2 in vivo |
| GO:0006513 protein monoubiquitination | IDA PMID:17938197 UBE2T, the Fanconi anemia core complex, and FANCD2 are recru... | ACCEPT | Summary: IDA annotation to protein monoubiquitination from the study establishing that FANCD2 monoubiquitination requires UBE2T and is regulated by chromatin localization. Reason: Core biological process; directly supported by the requirement of UBE2T for DNA-damage-restricted FANCD2 monoubiquitination. Supporting Evidence: PMID:17938197 FANCD2 monoubiquitination is therefore not regulated by multiprotein complex assembly but by the formation of an active E2/E3 holoenzyme on chromatin. |
| GO:0006513 protein monoubiquitination | IDA PMID:19111657 Mechanistic insight into site-restricted monoubiquitination ... | ACCEPT | Summary: IDA annotation to protein monoubiquitination from the minimal reconstitution showing FANCI restricts the modification to the physiological FANCD2 substrate lysine. Reason: Core biological process directly catalyzed by UBE2T with FANCL (site-specific FANCD2 monoubiquitination). Supporting Evidence: PMID:19111657 addition of the FANCI protein enhances monoubiquitination and also restricts it to the in vivo substrate lysine residue on FANCD2 |
| GO:0006974 DNA damage response | IMP PMID:16916645 UBE2T is the E2 in the Fanconi anemia pathway and undergoes ... | ACCEPT | Summary: IMP annotation to DNA damage response, from loss-of-function evidence linking UBE2T to the DNA-damage-activated FA pathway. Reason: UBE2T operates in the DNA-damage/replication-stress-activated FA pathway; its depletion produces the DNA-damage-induced chromosomal instability of FA. Consistent with the IBA DNA damage response annotation. Supporting Evidence: PMID:16916645 The Fanconi anemia pathway is required for the efficient repair of damaged DNA. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:16916645 UBE2T is the E2 in the Fanconi anemia pathway and undergoes ... | ACCEPT | Summary: IPI annotation for binding the E3 ubiquitin-protein ligase FANCL (Q9NW38), the cognate partner of UBE2T in the FA pathway. Reason: Informative and central: the UBE2T-FANCL E2-E3 interaction is required for FANCD2 monoubiquitination. FANCL is the RING E3 ligase subunit of the FA core complex. This is the informative counterpart to the generic 'protein binding' annotation. Supporting Evidence: PMID:16916645 UBE2T binds to FANCL, the ubiquitin ligase subunit of the Fanconi anemia core complex |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:17938197 UBE2T, the Fanconi anemia core complex, and FANCD2 are recru... | ACCEPT | Summary: IPI annotation for UBE2T binding the E3 ligase FANCL, forming the active E2/E3 holoenzyme on chromatin. Reason: Supported and functionally central; the FANCL interaction underlies UBE2T's role in FANCD2 monoubiquitination. Supporting Evidence: PMID:17938197 the formation of an active E2/E3 holoenzyme on chromatin |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:19111657 Mechanistic insight into site-restricted monoubiquitination ... | ACCEPT | Summary: IPI annotation for UBE2T-FANCL binding; the FANCL RWD-like domain stimulates the UBE2T-catalyzed reaction. Reason: Directly supported and central to function; FANCL binding is required for efficient FANCD2 monoubiquitination. Supporting Evidence: PMID:19111657 monoubiquitination is stimulated by a conserved RWD-like domain in FANCL |
| GO:0051865 protein autoubiquitination | IDA PMID:16916645 UBE2T is the E2 in the Fanconi anemia pathway and undergoes ... | KEEP AS NON CORE | Summary: IDA annotation to protein autoubiquitination: UBE2T undergoes automonoubiquitination (Lys-91), stimulated by FANCL, reported to inactivate the enzyme. Reason: Experimentally supported but a regulatory/self-limiting modification rather than UBE2T's core catalytic output (FANCD2/FANCI monoubiquitination). The functional consequence is also disputed between reports (PMID:16916645 inactivating; PMID:19111657 no effect). Retained as non-core. Supporting Evidence: PMID:16916645 UBE2T undergoes automonoubiquitination in vivo. This monoubiquitination is stimulated by the presence of the FANCL protein and inactivates UBE2T. |
| GO:0051865 protein autoubiquitination | IDA PMID:19111657 Mechanistic insight into site-restricted monoubiquitination ... | KEEP AS NON CORE | Summary: IDA annotation to protein autoubiquitination (Lys-91/Lys-182) from the mechanistic reconstitution study. Reason: Supported but regulatory and non-core; here autoubiquitination was reported not to affect E2 activity, underscoring that it is a modulatory feature rather than the enzyme's core function. |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:20061386 The E2 ubiquitin-conjugating enzymes direct polyubiquitinati... | MODIFY | Summary: IDA annotation to general ubiquitin-protein transferase activity from the systematic in-vitro characterization of all human E2 enzymes. Reason: Correct but too general; the E2-specific GO:0061631 (ubiquitin conjugating enzyme activity) more precisely captures UBE2T's molecular function. Proposed replacements: ubiquitin conjugating enzyme activity Supporting Evidence: PMID:20061386 the E2 enzymes are capable of directing the ubiquitination process to distinct subsets of ubiquitin lysines, depending on the specific E2 utilized |
| GO:0035519 protein K29-linked ubiquitination | IDA PMID:20061386 The E2 ubiquitin-conjugating enzymes direct polyubiquitinati... | MARK AS OVER ANNOTATED | Summary: IDA annotation to K29-linked ubiquitination from an in-vitro, E3-free assay of intrinsic E2 lysine preference. Reason: Derived from a systematic in-vitro study performed in the absence of an E3 ligase, measuring the intrinsic lysine preferences of purified E2s. This does not reflect UBE2T's physiological function (site-specific monoubiquitination of FANCD2/FANCI with FANCL); UniProt notes the all-seven-lysine polyubiquitination is an in-vitro capacity. Over-annotation of the biological role. Supporting Evidence: PMID:20061386 Because this study was performed in the absence of an E3 enzyme, our data indicate that the E2 enzymes are capable of directing the ubiquitination process to distinct subsets of ubiquitin lysines |
| GO:0044314 protein K27-linked ubiquitination | IDA PMID:20061386 The E2 ubiquitin-conjugating enzymes direct polyubiquitinati... | MARK AS OVER ANNOTATED | Summary: IDA annotation to K27-linked ubiquitination from the in-vitro, E3-free E2 lysine-preference assay. Reason: In-vitro capacity measured without an E3 ligase; not representative of UBE2T's physiological monoubiquitination role in the FA pathway. Over-annotation. Supporting Evidence: PMID:20061386 Because this study was performed in the absence of an E3 enzyme, our data indicate that the E2 enzymes are capable of directing the ubiquitination process to distinct subsets of ubiquitin lysines |
| GO:0070534 protein K63-linked ubiquitination | IDA PMID:20061386 The E2 ubiquitin-conjugating enzymes direct polyubiquitinati... | MARK AS OVER ANNOTATED | Summary: IDA annotation to K63-linked ubiquitination from the in-vitro, E3-free E2 lysine-preference assay. Reason: Reflects intrinsic in-vitro lysine preference measured without an E3; not the physiological FA-pathway function of UBE2T. Over-annotation of biological role. Supporting Evidence: PMID:20061386 Because this study was performed in the absence of an E3 enzyme, our data indicate that the E2 enzymes are capable of directing the ubiquitination process to distinct subsets of ubiquitin lysines |
| GO:0070936 protein K48-linked ubiquitination | IDA PMID:20061386 The E2 ubiquitin-conjugating enzymes direct polyubiquitinati... | MARK AS OVER ANNOTATED | Summary: IDA annotation to K48-linked ubiquitination from the in-vitro, E3-free E2 lysine-preference assay. Reason: In-vitro capacity determined in the absence of an E3 ligase; does not represent UBE2T's physiological function. Over-annotation of biological role. Supporting Evidence: PMID:20061386 Because this study was performed in the absence of an E3 enzyme, our data indicate that the E2 enzymes are capable of directing the ubiquitination process to distinct subsets of ubiquitin lysines |
| GO:0070979 protein K11-linked ubiquitination | IDA PMID:20061386 The E2 ubiquitin-conjugating enzymes direct polyubiquitinati... | MARK AS OVER ANNOTATED | Summary: IDA annotation to K11-linked ubiquitination from the in-vitro, E3-free E2 lysine-preference assay. Reason: Intrinsic in-vitro lysine preference measured without an E3; not the physiological monoubiquitination role of UBE2T. Over-annotation of biological role. Supporting Evidence: PMID:20061386 Because this study was performed in the absence of an E3 enzyme, our data indicate that the E2 enzymes are capable of directing the ubiquitination process to distinct subsets of ubiquitin lysines |
| GO:0085020 protein K6-linked ubiquitination | IDA PMID:20061386 The E2 ubiquitin-conjugating enzymes direct polyubiquitinati... | MARK AS OVER ANNOTATED | Summary: IDA annotation to K6-linked ubiquitination from the in-vitro, E3-free E2 lysine-preference assay. Reason: Reflects intrinsic in-vitro lysine usage measured without an E3 ligase; not representative of UBE2T's physiological FA-pathway function. Over-annotation. Supporting Evidence: PMID:20061386 Because this study was performed in the absence of an E3 enzyme, our data indicate that the E2 enzymes are capable of directing the ubiquitination process to distinct subsets of ubiquitin lysines |
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