MAD2L2 (also known as REV7 or MAD2B) is a HORMA domain-containing adapter protein with dual essential roles in DNA damage response. It functions as: (1) an accessory subunit of DNA polymerase zeta (Pol zeta), mediating translesion DNA synthesis by bridging the catalytic REV3L subunit with REV1 to bypass DNA lesions; and (2) a core component of the shieldin complex (SHLD1/SHLD2/SHLD3/REV7), which acts downstream of 53BP1-RIF1 to suppress DNA end resection, thereby promoting NHEJ over homologous recombination. The HORMA domain adopts open and closed conformations that enable high-affinity binding to partner proteins via a "safety-belt" mechanism. MAD2L2 also regulates cell cycle progression by inhibiting the APC/C through binding to CDH1 and CDC20. Biallelic loss causes Fanconi anemia complementation group V.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: REV7/MAD2L2 localizes to the nucleus where it performs its core functions in DNA damage response (translesion synthesis and DSB repair) and cell cycle regulation. Multiple studies confirm nuclear localization (PMID:11717438, PMID:17541814, PMID:17719540). Reason: Nuclear localization is well-established and consistent with REV7's roles in DNA polymerase zeta-mediated TLS and shieldin complex-mediated DSB repair. Supporting Evidence: PMID:11717438 the mitotic checkpoint protein MAD2B interacts with PRCC PMID:17541814 HCCA2 and MAD2L2 also colocalized in the nucleus of Hela cells |
| GO:0006281 DNA repair | IBA GO_REF:0000033 | ACCEPT | Summary: REV7 participates in DNA repair through multiple mechanisms: (1) as part of Pol zeta for translesion synthesis to bypass DNA lesions, and (2) as part of shieldin complex to regulate DSB repair pathway choice. Reason: DNA repair is a core function of REV7. The IBA annotation appropriately captures the general DNA repair role supported by extensive literature. Supporting Evidence: PMID:29656893 Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection and in sensitizing BRCA1-deficient cells to PARP inhibitors PMID:20164194 we show that the REV7-mediated interactions are responsible for DNA damage tolerance PMID:27500492 identified REV7 as a previously undescribed FA gene, which we term FANCV |
| GO:0016035 zeta DNA polymerase complex | IBA GO_REF:0000033 | ACCEPT | Summary: REV7 is an essential accessory subunit of DNA polymerase zeta. The minimal complex (Pol-zeta2) consists of REV3L and REV7; the fully active complex (Pol-zeta4) includes REV3L, REV7, POLD2, and POLD3. Reason: REV7 as a component of Pol zeta is one of its core, evolutionarily conserved functions from yeast to humans. Supporting Evidence: PMID:24449906 The purified four-subunit Pol zeta4 (Rev3-Rev7-PolD2-PolD3) is much more efficient and more processive PMID:11485998 Human REV7 (hREV7) was also cloned, and its product was found to interact with hREV3, but the biological function of hREV7 remained unknown file:human/MAD2L2/MAD2L2-deep-research-falcon.md REV7 is an accessory subunit of human Pol zeta together with the catalytic subunit REV3L and replicative subunits POLD2/POLD3; Pol zeta functions as the extender polymerase in translesion synthesis |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation based on UniProt subcellular location. Consistent with experimental evidence. Reason: The IEA annotation is redundant with the IBA annotation but correctly reflects the experimentally verified nuclear localization of REV7. Supporting Evidence: PMID:17541814 HCCA2 and MAD2L2 also colocalized in the nucleus of Hela cells |
| GO:0005694 chromosome | IEA GO_REF:0000044 | ACCEPT | Summary: REV7 is recruited to chromosomes, particularly at sites of DNA double-strand breaks during G1 and S phase as part of the shieldin complex. Reason: Chromosome localization is consistent with REV7's role in the shieldin complex for DSB repair. Supporting Evidence: PMID:29656893 Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168-53BP1-RIF1 axis |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Some cytoplasmic localization has been observed for REV7, though its primary functional localizations are nuclear. Reason: Cytoplasmic localization has been reported and is consistent with UniProt annotation, though nucleus is the primary site of function. Supporting Evidence: PMID:17719540 the Shigella effector IpaB, when delivered into epithelial cells, causes cell-cycle arrest by targeting Mad2L2 |
| GO:0005819 spindle | IEA GO_REF:0000044 | ACCEPT | Summary: REV7 localizes to the mitotic spindle through interaction with CHAMP1 and RAN, reflecting its role in cell cycle regulation. Reason: Spindle localization has been experimentally demonstrated and reflects REV7's secondary role in mitotic regulation. Supporting Evidence: PMID:21063390 CAMP localizes to chromosomes and the spindle including kinetochores |
| GO:0006281 DNA repair | IEA GO_REF:0000043 | ACCEPT | Summary: Electronic annotation based on UniProt keyword mapping. Correctly reflects REV7's role in DNA repair. Reason: Redundant with IBA annotation but correct. DNA repair is a well-established core function of REV7. Supporting Evidence: PMID:29656893 Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: REV7 modulates transcription through interaction with TCF4/TCF7L2 and the JNK-ELK1 pathway, but this is not a core function. Reason: Transcriptional regulation by REV7 is documented but represents a secondary pleiotropic effect rather than a core molecular function. Supporting Evidence: PMID:19443654 Thus, MAD2B is a novel TCF4-interacting protein PMID:17296730 hRev7 acts to promote Elk-1 phosphorylation by the c-Jun N-terminal protein kinase (JNK) MAP kinases |
| GO:0006974 DNA damage response | IEA GO_REF:0000043 | ACCEPT | Summary: REV7 is a key component of the DNA damage response through both TLS and DSB repair pathway choice. Reason: DNA damage response is accurately captured by this annotation. REV7 coordinates multiple aspects of cellular response to DNA damage. Supporting Evidence: PMID:17296730 our data linking hRev7 to gene expression changes suggest that hRev7 has a widespread role in coordinating the cellular response to DNA damage |
| GO:0010717 regulation of epithelial to mesenchymal transition | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: REV7 negatively regulates EMT through its interaction with TCF4, which modulates E-cadherin expression. Reason: EMT regulation by REV7 is documented experimentally but represents a secondary pleiotropic function mediated through TCF4 interaction, not a core function. Supporting Evidence: PMID:19443654 Knockdown of MAD2B in SW480 colorectal cancer cells led to the conversion of epithelial cells to a mesenchymal fibroblastoid phenotype |
| GO:0051301 cell division | IEA GO_REF:0000043 | ACCEPT | Summary: REV7 regulates cell division through inhibition of the APC/C and spindle-related functions. Reason: Cell division regulation is a core function of REV7 through its inhibition of APC/C activators CDH1 and CDC20. Supporting Evidence: PMID:11459826 MAD2B inhibits both CDH1-APC and CDC20-APC |
| GO:0005515 protein binding | IPI PMID:10527948 Evidence for an interaction of the metalloprotease-disintegr... | MARK AS OVER ANNOTATED | Summary: Interaction with ADAM9 (MDC9) demonstrated by yeast two-hybrid and confirmed biochemically. Reason: "Protein binding" is uninformative. The interaction with ADAM9 lacks clear functional significance and may be an artifact of Y2H screening. Supporting Evidence: PMID:10527948 a novel MAD2-related protein, MAD2beta, as a binding partner of the MDC9 cytoplasmic domain |
| GO:0005515 protein binding | IPI PMID:10531379 Interaction of the metalloprotease disintegrins MDC9 and MDC... | MARK AS OVER ANNOTATED | Summary: Another study on MDC9/ADAM9 interactions. Reason: "Protein binding" is uninformative for functional annotation purposes. Supporting Evidence: PMID:10527948 a novel MAD2-related protein, MAD2beta, as a binding partner of the MDC9 cytoplasmic domain |
| GO:0005515 protein binding | IPI PMID:11277934 Trichosanthin interacts with acidic ribosomal proteins P0 an... | MARK AS OVER ANNOTATED | Summary: Interaction with trichosanthin demonstrated. Reason: "Protein binding" is uninformative. Trichosanthin interaction lacks clear physiological relevance. Supporting Evidence: PMID:10527948 a novel MAD2-related protein, MAD2beta, as a binding partner of the MDC9 cytoplasmic domain |
| GO:0005515 protein binding | IPI PMID:17719540 A bacterial effector targets Mad2L2, an APC inhibitor, to mo... | MARK AS OVER ANNOTATED | Summary: Interaction with Shigella IpaB protein that modulates APC activity. Reason: "Protein binding" is uninformative. The interaction with bacterial effector IpaB is relevant for pathogenesis but not normal cellular function. Supporting Evidence: PMID:17719540 the Shigella effector IpaB, when delivered into epithelial cells, causes cell-cycle arrest by targeting Mad2L2 |
| GO:0005515 protein binding | IPI PMID:21063390 CAMP (C13orf8, ZNF828) is a novel regulator of kinetochore-m... | MARK AS OVER ANNOTATED | Summary: Interaction with CHAMP1 demonstrated, relevant to spindle function. Reason: "Protein binding" is uninformative. This interaction is functionally relevant but should be captured by more specific terms related to spindle function. Supporting Evidence: PMID:21063390 CAMP localizes to chromosomes and the spindle including kinetochores |
| GO:0005515 protein binding | IPI PMID:22828282 The C-terminal domain of human Rev1 contains independent bin... | MARK AS OVER ANNOTATED | Summary: Interaction with REV3L demonstrated by structural and biochemical studies. Reason: "Protein binding" is uninformative. The REV7-REV3L interaction is a core function but should be captured by the Pol zeta complex annotation. Supporting Evidence: PMID:20164194 REV7 interacts with both REV3 and REV1 polymerases |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: High-throughput interactome study. Reason: "Protein binding" from high-throughput studies lacks functional context. Supporting Evidence: PMID:20164194 REV7 interacts with both REV3 and REV1 polymerases |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | MARK AS OVER ANNOTATED | Summary: Quantitative interactome study. Reason: "Protein binding" from high-throughput studies lacks functional context. Supporting Evidence: PMID:20164194 REV7 interacts with both REV3 and REV1 polymerases |
| GO:0005515 protein binding | IPI PMID:29656893 DNA Repair Network Analysis Reveals Shieldin as a Key Regula... | MARK AS OVER ANNOTATED | Summary: Interaction with shieldin complex components (SHLD2, SHLD3) demonstrated. Reason: "Protein binding" is uninformative. These interactions are functionally critical and should be captured by process annotations for DSB repair. Supporting Evidence: PMID:29656893 We identified a novel vertebrate-specific protein complex, shieldin, comprising REV7 plus three previously uncharacterized proteins |
| GO:0005515 protein binding | IPI PMID:29789392 FAM35A associates with REV7 and modulates DNA damage respons... | MARK AS OVER ANNOTATED | Summary: Interaction with SHLD2/FAM35A demonstrated. Reason: "Protein binding" is uninformative. Captured by shieldin complex function annotations. Supporting Evidence: PMID:29656893 We identified a novel vertebrate-specific protein complex, shieldin, comprising REV7 plus three previously uncharacterized proteins |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Binary protein interactome study. Reason: "Protein binding" from high-throughput studies lacks functional context. Supporting Evidence: PMID:20164194 REV7 interacts with both REV3 and REV1 polymerases |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Neurodegenerative disease interactome study. Reason: "Protein binding" from high-throughput studies lacks functional context. Supporting Evidence: PMID:20164194 REV7 interacts with both REV3 and REV1 polymerases |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Nucleoplasm localization demonstrated by immunofluorescence. Reason: Nucleoplasm is a more specific localization consistent with REV7's nuclear functions in DNA repair. Supporting Evidence: PMID:17541814 HCCA2 and MAD2L2 also colocalized in the nucleus of Hela cells |
| GO:0042276 error-prone translesion synthesis | IDA PMID:24449906 Human Pol ΞΆ purified with accessory subunits is active in tr... | ACCEPT | Summary: REV7 as part of Pol zeta participates in error-prone translesion synthesis to bypass DNA lesions. Reason: This is a core function of REV7 as part of the DNA polymerase zeta complex. Error-prone TLS is the primary function of Pol zeta. Supporting Evidence: PMID:24449906 DNA polymerase zeta (Pol zeta) is a eukaryotic B-family DNA polymerase that specializes in translesion synthesis |
| GO:0005515 protein binding | IPI PMID:20164194 Crystal structure of human REV7 in complex with a human REV3... | MARK AS OVER ANNOTATED | Summary: Crystal structure shows REV7 binding to REV3L and REV1. Reason: "Protein binding" is uninformative. The specific adapter function is better captured by process annotations. Supporting Evidence: PMID:20164194 REV7 interacts with both REV3 and REV1 polymerases |
| GO:0090734 site of DNA damage | IDA PMID:29656893 DNA Repair Network Analysis Reveals Shieldin as a Key Regula... | ACCEPT | Summary: REV7 is recruited to sites of DNA damage as part of the shieldin complex. Reason: Localization to DNA damage sites is consistent with REV7's role in the shieldin complex for DSB repair. Supporting Evidence: PMID:29656893 Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168-53BP1-RIF1 axis |
| GO:0005515 protein binding | IPI PMID:23143872 Structural insights into the assembly of human translesion p... | MARK AS OVER ANNOTATED | Summary: Structural study of translesion polymerase complex assembly. Reason: "Protein binding" is uninformative. Captured by Pol zeta complex annotations. Supporting Evidence: PMID:20164194 we show the first crystal structure of human REV7 in complex with a fragment of human REV3 polymerase |
| GO:0019985 translesion synthesis | IDA PMID:20164194 Crystal structure of human REV7 in complex with a human REV3... | ACCEPT | Summary: REV7 mediates translesion synthesis as an adapter in the Pol zeta complex. Reason: This is a core function of REV7. The crystal structure and functional studies demonstrate REV7's essential role in TLS. Supporting Evidence: PMID:20164194 Our results highlight the function of REV7 as an adapter protein to recruit Polzeta to a lesion site |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:20164194 Crystal structure of human REV7 in complex with a human REV3... | ACCEPT | Summary: REV7 functions as an adapter protein bridging REV3L and REV1 in the Pol zeta complex. Reason: This accurately captures REV7's molecular function. The HORMA domain mediates adapter function through safety-belt mechanism. Supporting Evidence: PMID:20164194 Our results highlight the function of REV7 as an adapter protein to recruit Polzeta to a lesion site |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:19443654 MAD2B, a novel TCF4-binding protein, modulates TCF4-mediated... | KEEP AS NON CORE | Summary: REV7 negatively regulates TCF4-mediated transcription by preventing DNA binding. Reason: This is a documented function but represents a secondary pleiotropic effect rather than a core molecular function of REV7. Supporting Evidence: PMID:19443654 Using the TOPFLASH reporter assay, we found that MAD2B blocks TCF4-mediated transactivation |
| GO:0003714 transcription corepressor activity | IMP PMID:19443654 MAD2B, a novel TCF4-binding protein, modulates TCF4-mediated... | KEEP AS NON CORE | Summary: REV7 acts as a transcription corepressor by inhibiting TCF4 DNA binding. Reason: While experimentally demonstrated, transcription corepressor activity is a secondary function not directly related to REV7's core roles in DNA repair and cell cycle regulation. Supporting Evidence: PMID:19443654 Using the TOPFLASH reporter assay, we found that MAD2B blocks TCF4-mediated transactivation |
| GO:0000785 chromatin | NAS PMID:29656893 DNA Repair Network Analysis Reveals Shieldin as a Key Regula... | ACCEPT | Summary: REV7 associates with chromatin as part of the shieldin complex at DSB sites. Reason: Chromatin association is consistent with REV7's role in DSB repair as part of the shieldin complex. Supporting Evidence: PMID:29656893 Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168-53BP1-RIF1 axis |
| GO:0002208 somatic diversification of immunoglobulins involved in immune response | NAS PMID:29656893 DNA Repair Network Analysis Reveals Shieldin as a Key Regula... | ACCEPT | Summary: REV7 in the shieldin complex promotes immunoglobulin class-switch recombination. Reason: CSR is a physiologically important function of the shieldin complex where REV7 is essential. Supporting Evidence: PMID:29656893 promotes NHEJ-dependent repair of intrachromosomal breaks, immunoglobulin class-switch recombination (CSR), and fusion of unprotected telomeres |
| GO:0035861 site of double-strand break | NAS PMID:29656893 DNA Repair Network Analysis Reveals Shieldin as a Key Regula... | ACCEPT | Summary: REV7 is recruited to DSB sites as part of the shieldin complex. Reason: DSB site localization is consistent with shieldin complex function in suppressing DNA end resection. Supporting Evidence: PMID:29656893 Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168-53BP1-RIF1 axis |
| GO:0043247 telomere maintenance in response to DNA damage | NAS PMID:29656893 DNA Repair Network Analysis Reveals Shieldin as a Key Regula... | ACCEPT | Summary: REV7 as part of shieldin promotes fusion of unprotected telomeres. Reason: Telomere maintenance is a documented function of the shieldin complex. Supporting Evidence: PMID:29656893 promotes NHEJ-dependent repair of intrachromosomal breaks, immunoglobulin class-switch recombination (CSR), and fusion of unprotected telomeres |
| GO:2001034 positive regulation of double-strand break repair via nonhomologous end joining | NAS PMID:29656893 DNA Repair Network Analysis Reveals Shieldin as a Key Regula... | ACCEPT | Summary: REV7 in shieldin complex promotes NHEJ by suppressing DNA end resection. Reason: This is a core function of REV7 as part of the shieldin complex. Supporting Evidence: PMID:29656893 Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection |
| GO:0005515 protein binding | IPI PMID:34354233 ASTE1 promotes shieldin-complex-mediated DNA repair by atten... | MARK AS OVER ANNOTATED | Summary: Interaction with ASTE1 demonstrated. Reason: "Protein binding" is uninformative. The ASTE1 interaction relates to shieldin function but should be captured by process terms. Supporting Evidence: PMID:29656893 We identified a novel vertebrate-specific protein complex, shieldin, comprising REV7 plus three previously uncharacterized proteins |
| GO:0005694 chromosome | IC PMID:29656893 DNA Repair Network Analysis Reveals Shieldin as a Key Regula... | ACCEPT | Summary: Inferred chromosome localization based on shieldin complex function. Reason: Chromosome localization is consistent with REV7's role in DSB repair. Supporting Evidence: PMID:29656893 Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168-53BP1-RIF1 axis |
| GO:0035861 site of double-strand break | IC PMID:29656893 DNA Repair Network Analysis Reveals Shieldin as a Key Regula... | ACCEPT | Summary: Inferred localization to DSB sites. Reason: Consistent with shieldin complex function and experimental evidence. Supporting Evidence: PMID:29656893 Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168-53BP1-RIF1 axis |
| GO:0045830 positive regulation of isotype switching | IDA PMID:29656893 DNA Repair Network Analysis Reveals Shieldin as a Key Regula... | ACCEPT | Summary: REV7 in shieldin complex is required for immunoglobulin class-switch recombination. Reason: CSR regulation is a documented physiological function of the shieldin complex. Supporting Evidence: PMID:29656893 promotes NHEJ-dependent repair of intrachromosomal breaks, immunoglobulin class-switch recombination (CSR), and fusion of unprotected telomeres |
| GO:2000042 negative regulation of double-strand break repair via homologous recombination | IDA PMID:29656893 DNA Repair Network Analysis Reveals Shieldin as a Key Regula... | ACCEPT | Summary: REV7 in shieldin complex suppresses HR by inhibiting DNA end resection. Reason: This is a core function of REV7. By promoting NHEJ, the shieldin complex antagonizes HR. Supporting Evidence: PMID:29656893 Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection |
| GO:2001034 positive regulation of double-strand break repair via nonhomologous end joining | IDA PMID:29656893 DNA Repair Network Analysis Reveals Shieldin as a Key Regula... | ACCEPT | Summary: REV7 in shieldin complex promotes NHEJ. Reason: This is a core function of REV7 as part of the shieldin complex. Supporting Evidence: PMID:29656893 Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-110311 | ACCEPT | Summary: Reactome pathway annotation for Pol zeta function in nucleoplasm. Reason: Nucleoplasm localization is consistent with TLS and DSB repair functions. Supporting Evidence: PMID:24449906 DNA polymerase zeta (Pol zeta) is a eukaryotic B-family DNA polymerase that specializes in translesion synthesis |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-110322 | ACCEPT | Summary: Reactome pathway annotation for Pol zeta complex formation. Reason: Consistent with REV7 function in Pol zeta. Supporting Evidence: PMID:24449906 At a minimum, Pol zeta consists of a catalytic subunit Rev3 and an accessory subunit Rev7 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5652151 | ACCEPT | Summary: Reactome annotation for REV1 recruiting Pol zeta. Reason: Consistent with TLS function. Supporting Evidence: PMID:20164194 Our results highlight the function of REV7 as an adapter protein to recruit Polzeta to a lesion site |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5655835 | ACCEPT | Summary: Reactome annotation for POLK-REV1-POLZ complex. Reason: Consistent with TLS function. Supporting Evidence: PMID:20164194 Our results highlight the function of REV7 as an adapter protein to recruit Polzeta to a lesion site |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5655892 | ACCEPT | Summary: Reactome annotation for POLK nucleotide incorporation. Reason: Consistent with TLS pathway. Supporting Evidence: PMID:24449906 DNA polymerase zeta (Pol zeta) is a eukaryotic B-family DNA polymerase that specializes in translesion synthesis |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5655965 | ACCEPT | Summary: Reactome annotation for POLK-POLZ cooperation. Reason: Consistent with TLS function. Supporting Evidence: PMID:24449906 The purified four-subunit Pol zeta4 (Rev3-Rev7-PolD2-PolD3) is much more efficient and more processive |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5656105 | ACCEPT | Summary: Reactome annotation for POLI binding REV1 and PCNA. Reason: Consistent with TLS pathway. Supporting Evidence: PMID:20164194 REV7 interacts with both REV3 and REV1 polymerases |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5656148 | ACCEPT | Summary: Reactome annotation for POLI nucleotide incorporation. Reason: Consistent with TLS pathway. Supporting Evidence: PMID:24449906 DNA polymerase zeta (Pol zeta) is a eukaryotic B-family DNA polymerase that specializes in translesion synthesis |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5656158 | ACCEPT | Summary: Reactome annotation for POLZ elongation of POLI product. Reason: Consistent with TLS function where REV7-containing Pol zeta extends. Supporting Evidence: PMID:24449906 The purified four-subunit Pol zeta4 (Rev3-Rev7-PolD2-PolD3) is much more efficient and more processive |
| GO:0005634 nucleus | IDA PMID:19443654 MAD2B, a novel TCF4-binding protein, modulates TCF4-mediated... | ACCEPT | Summary: Nuclear localization demonstrated experimentally. Reason: Nuclear localization is well-established for REV7. Supporting Evidence: PMID:17541814 HCCA2 and MAD2L2 also colocalized in the nucleus of Hela cells |
| GO:0007015 actin filament organization | IMP PMID:19443654 MAD2B, a novel TCF4-binding protein, modulates TCF4-mediated... | KEEP AS NON CORE | Summary: REV7 knockdown affects actin organization as part of EMT phenotype. Reason: This is an indirect effect through REV7's modulation of TCF4-mediated transcription, not a direct molecular function. Supporting Evidence: PMID:19443654 Mesenchymal induction was accompanied by F-actin redistribution and the appearance of a fibroblastoid phenotype |
| GO:0010719 negative regulation of epithelial to mesenchymal transition | IMP PMID:19443654 MAD2B, a novel TCF4-binding protein, modulates TCF4-mediated... | KEEP AS NON CORE | Summary: REV7 negatively regulates EMT by modulating TCF4 activity. Reason: This is a secondary pleiotropic effect through TCF4 interaction. Supporting Evidence: PMID:19443654 Knockdown of MAD2B in SW480 colorectal cancer cells led to the conversion of epithelial cells to a mesenchymal fibroblastoid phenotype |
| GO:0010944 negative regulation of transcription by competitive promoter binding | IMP PMID:19443654 MAD2B, a novel TCF4-binding protein, modulates TCF4-mediated... | KEEP AS NON CORE | Summary: REV7 binding to TCF4 abolishes TCF4 DNA binding ability. Reason: This mechanism explains how REV7 inhibits TCF4 function but is a secondary role. Supporting Evidence: PMID:19443654 TCF4 and MAD2B interactions abolished the DNA binding ability of TCF4 |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IPI PMID:19443654 MAD2B, a novel TCF4-binding protein, modulates TCF4-mediated... | KEEP AS NON CORE | Summary: REV7 binds to TCF4/TCF7L2 transcription factor. Reason: This interaction is documented but represents a secondary function. Supporting Evidence: PMID:19443654 Thus, MAD2B is a novel TCF4-interacting protein |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IMP PMID:19443654 MAD2B, a novel TCF4-binding protein, modulates TCF4-mediated... | KEEP AS NON CORE | Summary: REV7 inhibits Wnt signaling by blocking TCF4 transcriptional activity. Reason: This is an indirect effect through TCF4 inhibition, a secondary function. Supporting Evidence: PMID:19443654 Using the TOPFLASH reporter assay, we found that MAD2B blocks TCF4-mediated transactivation |
| GO:2000048 negative regulation of cell-cell adhesion mediated by cadherin | IMP PMID:19443654 MAD2B, a novel TCF4-binding protein, modulates TCF4-mediated... | KEEP AS NON CORE | Summary: REV7 knockdown affects E-cadherin expression through TCF4. Reason: Indirect effect through TCF4 modulation. Supporting Evidence: PMID:19443654 MAD2B knockdown blocked E-cadherin expression |
| GO:0005515 protein binding | IPI PMID:11717438 Impairment of MAD2B-PRCC interaction in mitotic checkpoint d... | MARK AS OVER ANNOTATED | Summary: Interaction with PRCC demonstrated. Reason: "Protein binding" is uninformative. PRCC interaction has unclear functional significance. Supporting Evidence: PMID:11717438 the mitotic checkpoint protein MAD2B interacts with PRCC |
| GO:0005515 protein binding | IPI PMID:17541814 Hepatocellular carcinoma-associated gene 2 interacts with MA... | MARK AS OVER ANNOTATED | Summary: Interaction with YY1AP1 demonstrated. Reason: "Protein binding" is uninformative. Supporting Evidence: PMID:17541814 a novel HCCA2-interacting protein, MAD2L2 |
| GO:0005634 nucleus | IDA PMID:17541814 Hepatocellular carcinoma-associated gene 2 interacts with MA... | ACCEPT | Summary: Nuclear localization demonstrated. Reason: Consistent with other studies showing nuclear localization. Supporting Evidence: PMID:17541814 HCCA2 and MAD2L2 also colocalized in the nucleus of Hela cells |
| GO:0005515 protein binding | IPI PMID:11459826 MAD2B is an inhibitor of the anaphase-promoting complex. | MARK AS OVER ANNOTATED | Summary: Interaction with CDC20 and CDH1/FZR1 demonstrated. Reason: "Protein binding" is uninformative. The functional consequence (APC inhibition) is captured by other annotations. Supporting Evidence: PMID:11459826 MAD2B inhibits both CDH1-APC and CDC20-APC. This inhibition is targeted to CDH1 and CDC20 |
| GO:0042177 negative regulation of protein catabolic process | IDA PMID:11459826 MAD2B is an inhibitor of the anaphase-promoting complex. | ACCEPT | Summary: REV7 inhibits APC-mediated protein degradation by binding CDH1/CDC20. Reason: This captures the functional consequence of APC inhibition - prevention of ubiquitin-mediated protein degradation. Supporting Evidence: PMID:11459826 MAD2B also inhibits APC PMID:11459825 MAD2L2 specifically binds and inhibits Cdh1-APC, paralleling the effect of MAD2 on Cdc20 |
| GO:1904667 negative regulation of ubiquitin protein ligase activity | IDA PMID:11459826 MAD2B is an inhibitor of the anaphase-promoting complex. | ACCEPT | Summary: REV7 inhibits APC/C ubiquitin ligase activity through CDH1/CDC20. Reason: This is a core function of REV7 in cell cycle regulation. Supporting Evidence: PMID:11459826 MAD2B inhibits both CDH1-APC and CDC20-APC |
| GO:0005515 protein binding | IPI PMID:17296730 Rev7/MAD2B links c-Jun N-terminal protein kinase pathway sig... | MARK AS OVER ANNOTATED | Summary: Interaction with ELK1 demonstrated. Reason: "Protein binding" is uninformative. JNK binding term provides more specificity. Supporting Evidence: PMID:17296730 human Rev7 (hRev7)/MAD2B/MAD2L2 as an interaction partner for Elk-1 |
| GO:0005680 anaphase-promoting complex | IDA PMID:11459825 Inhibition of Cdh1-APC by the MAD2-related protein MAD2L2: a... | ACCEPT | Summary: REV7 colocalizes with the APC through interaction with CDH1. Reason: Physical association with APC is consistent with REV7's role in APC inhibition. Supporting Evidence: PMID:11459825 MAD2L2 specifically binds and inhibits Cdh1-APC, paralleling the effect of MAD2 on Cdc20 |
| GO:0008432 JUN kinase binding | IDA PMID:17296730 Rev7/MAD2B links c-Jun N-terminal protein kinase pathway sig... | KEEP AS NON CORE | Summary: REV7 binds JNK kinases to facilitate ELK1 phosphorylation. Reason: JNK binding is documented but represents a secondary signaling function. Supporting Evidence: PMID:17296730 hRev7 acts to promote Elk-1 phosphorylation by the c-Jun N-terminal protein kinase (JNK) MAP kinases |
| GO:0033138 positive regulation of peptidyl-serine phosphorylation | IDA PMID:17296730 Rev7/MAD2B links c-Jun N-terminal protein kinase pathway sig... | KEEP AS NON CORE | Summary: REV7 promotes ELK1 serine phosphorylation through JNK pathway. Reason: This is a secondary signaling function related to DNA damage response. Supporting Evidence: PMID:17296730 hRev7 acts to promote Elk-1 phosphorylation |
| GO:0042772 DNA damage response, signal transduction resulting in transcription | IDA PMID:17296730 Rev7/MAD2B links c-Jun N-terminal protein kinase pathway sig... | KEEP AS NON CORE | Summary: REV7 links DNA damage to transcriptional changes through JNK-ELK1 pathway. Reason: While related to DNA damage response, this signaling role is secondary to the core TLS and DSB repair functions. Supporting Evidence: PMID:17296730 hRev7 therefore contributes to the upregulation of Elk-1 target genes, such as egr-1, following exposure of cells to stress conditions caused by DNA-damaging agents |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:17296730 Rev7/MAD2B links c-Jun N-terminal protein kinase pathway sig... | KEEP AS NON CORE | Summary: REV7 promotes transcription through ELK1 activation. Reason: Secondary signaling function. Supporting Evidence: PMID:17296730 hRev7 therefore contributes to the upregulation of Elk-1 target genes |
| GO:0001558 regulation of cell growth | IGI PMID:15988022 Multiple roles of vertebrate REV genes in DNA repair and rec... | KEEP AS NON CORE | Summary: REV gene disruption in chicken DT40 cells affects cell growth. Reason: Cell growth regulation is an indirect consequence of REV7's roles in DNA repair and cell cycle control. Supporting Evidence: PMID:15988022 REV1-/- REV3-/- REV7-/- cells showed spontaneous cell death, chromosomal instability/fragility |
| GO:0006302 double-strand break repair | IGI PMID:15988022 Multiple roles of vertebrate REV genes in DNA repair and rec... | ACCEPT | Summary: REV7 participates in DSB repair in vertebrate cells. Reason: DSB repair is a core function of REV7 through the shieldin complex. Supporting Evidence: PMID:15988022 REV1-/- REV3-/- REV7-/- cells showed spontaneous cell death, chromosomal instability/fragility PMID:29656893 Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection |
| GO:0016035 zeta DNA polymerase complex | IDA PMID:20164194 Crystal structure of human REV7 in complex with a human REV3... | ACCEPT | Summary: Crystal structure demonstrates REV7 as part of the Pol zeta complex. Reason: This is a core molecular function - REV7 as an essential subunit of Pol zeta. Supporting Evidence: PMID:20164194 we show the first crystal structure of human REV7 in complex with a fragment of human REV3 polymerase |
| GO:0005819 spindle | IDA PMID:21063390 CAMP (C13orf8, ZNF828) is a novel regulator of kinetochore-m... | ACCEPT | Summary: REV7 localizes to spindle through CHAMP1 interaction. Reason: Spindle localization is consistent with REV7's role in cell cycle regulation. Supporting Evidence: PMID:21063390 CAMP localizes to chromosomes and the spindle including kinetochores |
| GO:0005515 protein binding | IPI PMID:20850016 Quantitative interaction proteomics and genome-wide profilin... | MARK AS OVER ANNOTATED | Summary: Interaction with POGZ demonstrated in epigenetic study. Reason: "Protein binding" is uninformative. Supporting Evidence: PMID:20164194 REV7 interacts with both REV3 and REV1 polymerases |
| GO:0005515 protein binding | IPI PMID:11485998 Interactions in the error-prone postreplication repair prote... | MARK AS OVER ANNOTATED | Summary: Interaction with REV1 and REV3 demonstrated. Reason: "Protein binding" is uninformative. The functional consequence (TLS) is captured by process annotations. Supporting Evidence: PMID:11485998 The interaction between hREV1 and hREV7 was identified by the yeast two-hybrid library screening |
| GO:0007094 mitotic spindle assembly checkpoint signaling | TAS PMID:10366450 Characterization of MAD2B and other mitotic spindle checkpoi... | MARK AS OVER ANNOTATED | Summary: MAD2L2 was originally identified as a MAD2 homolog with potential checkpoint function. Reason: Despite the gene name (MAD2L2), REV7 does not function in the spindle assembly checkpoint like MAD2. The original characterization was based on sequence homology, not functional evidence. REV7's primary roles are in TLS and DSB repair. Supporting Evidence: PMID:10366450 we isolated a novel human gene, MAD2B (MAD2L2), which is homologous to the spindle checkpoint gene MAD2 PMID:11459826 Unlike MAD2, whose interaction with MAD1 is required for mitotic checkpoint control, MAD2B does not interact with MAD1 |
| GO:0110027 negative regulation of DNA strand resection involved in replication fork processing | IMP PMID:36075897 MAD2L2 promotes replication fork protection and recovery in ... | NEW | Summary: Beyond its shieldin role at double-strand breaks, MAD2L2/REV7 protects stalled/reversed replication forks by limiting MRE11-dependent nucleolytic resection of nascent DNA and promoting fork restart. This fork-protection activity is independent of shieldin and instead requires the Pol zeta partners REV3L and REV1. Reason: Well-evidenced function (Paniagua et al. 2022, Nat Commun) not present in GOA or previously captured in this review. MAD2L2 depletion causes uncontrolled MRE11-dependent resection of stalled forks; fork protection is unaffected by loss of shieldin subunits but abolished by REV3L/REV1 loss, defining a distinct shieldin-independent, Pol zeta-associated fork-protection role. GO:0110027 is the correctly-branched biological-process term for negative regulation of resection during replication fork processing. Supporting Evidence: PMID:36075897 this function of MAD2L2 at replication forks is independent of its interaction with shieldin, but instead requires the TLS factors REV3L and REV1 PMID:36075897 uncontrolled MRE11-dependent resection of stalled forks |
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Download this section (compressed HTML)Q: How is REV7 partitioned between its roles in Pol zeta versus the shieldin complex?
Q: What determines whether REV7 functions in TLS versus DSB repair pathway choice?
Q: How does TRIP13/p31comet regulate REV7 complex disassembly?
Experiment: Structure-function analysis of REV7 mutants that selectively disrupt TLS versus shieldin functions
Hypothesis: Separation-of-function mutations can be identified that distinguish REV7's dual roles
Experiment: Live-cell imaging to track REV7 dynamics at DNA damage sites
Hypothesis: REV7 shows distinct recruitment kinetics to replication-associated versus DSB damage
Experiment: Characterization of REV7 post-translational modifications that regulate complex assembly
Hypothesis: Specific PTMs control whether REV7 assembles with Pol zeta or shieldin components
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