id: Q9UI95
gene_symbol: MAD2L2
aliases:
  - REV7
  - MAD2B
  - FANCV
  - hREV7
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.

core_functions:
  - molecular_function:
      id: GO:0030674
      label: protein-macromolecule adaptor activity
    description: >-
      REV7/MAD2L2 is an essential accessory subunit of DNA polymerase zeta that mediates
      translesion DNA synthesis. It bridges REV3L (the catalytic subunit) with REV1,
      enabling bypass of DNA lesions during replication. This adapter function requires
      REV7 dimerization and the HORMA domain safety-belt mechanism.
    directly_involved_in:
      - id: GO:0019985
        label: translesion synthesis
    in_complex:
      id: GO:0016035
      label: zeta DNA polymerase complex
    supported_by:
      - reference_id: PMID:20164194
        supporting_text: "Our results highlight the function of REV7 as an adapter protein to recruit Polzeta to a lesion site"
      - reference_id: PMID:24449906
        supporting_text: "At a minimum, Pol zeta consists of a catalytic subunit Rev3 and an accessory subunit Rev7"
      - reference_id: file:human/MAD2L2/MAD2L2-deep-research-falcon.md
        supporting_text: "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"

  - molecular_function:
      id: GO:0030674
      label: protein-macromolecule adaptor activity
    description: >-
      As a core component of the shieldin complex, REV7 promotes NHEJ by suppressing DNA
      end resection at double-strand breaks. The shieldin complex (SHLD1/SHLD2/SHLD3/REV7)
      acts downstream of 53BP1-RIF1 to shield DSB ends from nucleolytic processing, thereby
      favoring NHEJ over homologous recombination.
    directly_involved_in:
      - id: GO:2001034
        label: positive regulation of double-strand break repair via nonhomologous end joining
      - id: GO:2000042
        label: negative regulation of double-strand break repair via homologous recombination
    locations:
      - id: GO:0035861
        label: site of double-strand break
    supported_by:
      - reference_id: PMID:29656893
        supporting_text: "We identified a novel vertebrate-specific protein complex, shieldin, comprising REV7 plus three previously uncharacterized proteins"
      - reference_id: file:human/MAD2L2/MAD2L2-deep-research-falcon.md
        supporting_text: "REV7 is core to the SHLD1/SHLD2/SHLD3 complex that acts downstream of 53BP1 to limit 5' end resection, favoring classical NHEJ over HR at double-strand breaks"

  - molecular_function:
      id: GO:0030674
      label: protein-macromolecule adaptor activity
    description: >-
      REV7/MAD2L2 inhibits the anaphase-promoting complex (APC/C) by binding to and
      sequestering its activators CDH1 and CDC20. This represents a mechanism for
      regulating cell cycle progression.
    directly_involved_in:
      - id: GO:1904667
        label: negative regulation of ubiquitin protein ligase activity
      - id: GO:0051301
        label: cell division
    in_complex:
      id: GO:0005680
      label: anaphase-promoting complex
    supported_by:
      - reference_id: PMID:11459826
        supporting_text: "MAD2B also inhibits APC. In contrast to MAD2, MAD2B inhibits both CDH1-APC and CDC20-APC"
      - reference_id: PMID:11459825
        supporting_text: "MAD2L2 specifically binds and inhibits Cdh1-APC, paralleling the effect of MAD2 on Cdc20"

existing_annotations:
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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).
      action: ACCEPT
      reason: >-
        Nuclear localization is well-established and consistent with REV7's roles in
        DNA polymerase zeta-mediated TLS and shieldin complex-mediated DSB repair.
      supported_by:
        - reference_id: PMID:11717438
          supporting_text: "the mitotic checkpoint protein MAD2B interacts with PRCC"
        - reference_id: PMID:17541814
          supporting_text: "HCCA2 and MAD2L2 also colocalized in the nucleus of Hela cells"

  - term:
      id: GO:0006281
      label: DNA repair
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      reason: >-
        DNA repair is a core function of REV7. The IBA annotation appropriately captures
        the general DNA repair role supported by extensive literature.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection and in sensitizing BRCA1-deficient cells to PARP inhibitors"
        - reference_id: PMID:20164194
          supporting_text: "we show that the REV7-mediated interactions are responsible for DNA damage tolerance"
        - reference_id: PMID:27500492
          supporting_text: "identified REV7 as a previously undescribed FA gene, which we term FANCV"

  - term:
      id: GO:0016035
      label: zeta DNA polymerase complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      reason: >-
        REV7 as a component of Pol zeta is one of its core, evolutionarily conserved
        functions from yeast to humans.
      supported_by:
        - reference_id: PMID:24449906
          supporting_text: "The purified four-subunit Pol zeta4 (Rev3-Rev7-PolD2-PolD3) is much more efficient and more processive"
        - reference_id: PMID:11485998
          supporting_text: "Human REV7 (hREV7) was also cloned, and its product was found to interact with hREV3, but the biological function of hREV7 remained unknown"
        - reference_id: file:human/MAD2L2/MAD2L2-deep-research-falcon.md
          supporting_text: "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"

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        Electronic annotation based on UniProt subcellular location. Consistent with
        experimental evidence.
      action: ACCEPT
      reason: >-
        The IEA annotation is redundant with the IBA annotation but correctly reflects
        the experimentally verified nuclear localization of REV7.
      supported_by:
        - reference_id: PMID:17541814
          supporting_text: "HCCA2 and MAD2L2 also colocalized in the nucleus of Hela cells"

  - term:
      id: GO:0005694
      label: chromosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      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.
      action: ACCEPT
      reason: >-
        Chromosome localization is consistent with REV7's role in the shieldin complex
        for DSB repair.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168-53BP1-RIF1 axis"

  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        Some cytoplasmic localization has been observed for REV7, though its primary
        functional localizations are nuclear.
      action: ACCEPT
      reason: >-
        Cytoplasmic localization has been reported and is consistent with UniProt
        annotation, though nucleus is the primary site of function.
      supported_by:
        - reference_id: PMID:17719540
          supporting_text: "the Shigella effector IpaB, when delivered into epithelial cells, causes cell-cycle arrest by targeting Mad2L2"

  - term:
      id: GO:0005819
      label: spindle
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        REV7 localizes to the mitotic spindle through interaction with CHAMP1 and RAN,
        reflecting its role in cell cycle regulation.
      action: ACCEPT
      reason: >-
        Spindle localization has been experimentally demonstrated and reflects REV7's
        secondary role in mitotic regulation.
      supported_by:
        - reference_id: PMID:21063390
          supporting_text: "CAMP localizes to chromosomes and the spindle including kinetochores"

  - term:
      id: GO:0006281
      label: DNA repair
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        Electronic annotation based on UniProt keyword mapping. Correctly reflects
        REV7's role in DNA repair.
      action: ACCEPT
      reason: >-
        Redundant with IBA annotation but correct. DNA repair is a well-established
        core function of REV7.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection"

  - term:
      id: GO:0006351
      label: DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        REV7 modulates transcription through interaction with TCF4/TCF7L2 and the
        JNK-ELK1 pathway, but this is not a core function.
      action: KEEP_AS_NON_CORE
      reason: >-
        Transcriptional regulation by REV7 is documented but represents a secondary
        pleiotropic effect rather than a core molecular function.
      supported_by:
        - reference_id: PMID:19443654
          supporting_text: "Thus, MAD2B is a novel TCF4-interacting protein"
        - reference_id: PMID:17296730
          supporting_text: "hRev7 acts to promote Elk-1 phosphorylation by the c-Jun N-terminal protein kinase (JNK) MAP kinases"

  - term:
      id: GO:0006974
      label: DNA damage response
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        REV7 is a key component of the DNA damage response through both TLS and
        DSB repair pathway choice.
      action: ACCEPT
      reason: >-
        DNA damage response is accurately captured by this annotation. REV7 coordinates
        multiple aspects of cellular response to DNA damage.
      supported_by:
        - reference_id: PMID:17296730
          supporting_text: "our data linking hRev7 to gene expression changes suggest that hRev7 has a widespread role in coordinating the cellular response to DNA damage"

  - term:
      id: GO:0010717
      label: regulation of epithelial to mesenchymal transition
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        REV7 negatively regulates EMT through its interaction with TCF4, which modulates
        E-cadherin expression.
      action: KEEP_AS_NON_CORE
      reason: >-
        EMT regulation by REV7 is documented experimentally but represents a secondary
        pleiotropic function mediated through TCF4 interaction, not a core function.
      supported_by:
        - reference_id: PMID:19443654
          supporting_text: "Knockdown of MAD2B in SW480 colorectal cancer cells led to the conversion of epithelial cells to a mesenchymal fibroblastoid phenotype"

  - term:
      id: GO:0051301
      label: cell division
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        REV7 regulates cell division through inhibition of the APC/C and spindle-related
        functions.
      action: ACCEPT
      reason: >-
        Cell division regulation is a core function of REV7 through its inhibition of
        APC/C activators CDH1 and CDC20.
      supported_by:
        - reference_id: PMID:11459826
          supporting_text: "MAD2B inhibits both CDH1-APC and CDC20-APC"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10527948
    review:
      summary: >-
        Interaction with ADAM9 (MDC9) demonstrated by yeast two-hybrid and confirmed
        biochemically.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative. The interaction with ADAM9 lacks clear
        functional significance and may be an artifact of Y2H screening.
      supported_by:
        - reference_id: PMID:10527948
          supporting_text: "a novel MAD2-related protein, MAD2beta, as a binding partner of the MDC9 cytoplasmic domain"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10531379
    review:
      summary: >-
        Another study on MDC9/ADAM9 interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative for functional annotation purposes.
      supported_by:
        - reference_id: PMID:10527948
          supporting_text: "a novel MAD2-related protein, MAD2beta, as a binding partner of the MDC9 cytoplasmic domain"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11277934
    review:
      summary: >-
        Interaction with trichosanthin demonstrated.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative. Trichosanthin interaction lacks clear
        physiological relevance.
      supported_by:
        - reference_id: PMID:10527948
          supporting_text: "a novel MAD2-related protein, MAD2beta, as a binding partner of the MDC9 cytoplasmic domain"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17719540
    review:
      summary: >-
        Interaction with Shigella IpaB protein that modulates APC activity.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative. The interaction with bacterial effector
        IpaB is relevant for pathogenesis but not normal cellular function.
      supported_by:
        - reference_id: PMID:17719540
          supporting_text: "the Shigella effector IpaB, when delivered into epithelial cells, causes cell-cycle arrest by targeting Mad2L2"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21063390
    review:
      summary: >-
        Interaction with CHAMP1 demonstrated, relevant to spindle function.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative. This interaction is functionally relevant
        but should be captured by more specific terms related to spindle function.
      supported_by:
        - reference_id: PMID:21063390
          supporting_text: "CAMP localizes to chromosomes and the spindle including kinetochores"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22828282
    review:
      summary: >-
        Interaction with REV3L demonstrated by structural and biochemical studies.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative. The REV7-REV3L interaction is a core
        function but should be captured by the Pol zeta complex annotation.
      supported_by:
        - reference_id: PMID:20164194
          supporting_text: "REV7 interacts with both REV3 and REV1 polymerases"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25416956
    review:
      summary: >-
        High-throughput interactome study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" from high-throughput studies lacks functional context.
      supported_by:
        - reference_id: PMID:20164194
          supporting_text: "REV7 interacts with both REV3 and REV1 polymerases"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26496610
    review:
      summary: >-
        Quantitative interactome study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" from high-throughput studies lacks functional context.
      supported_by:
        - reference_id: PMID:20164194
          supporting_text: "REV7 interacts with both REV3 and REV1 polymerases"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29656893
    review:
      summary: >-
        Interaction with shieldin complex components (SHLD2, SHLD3) demonstrated.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative. These interactions are functionally
        critical and should be captured by process annotations for DSB repair.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "We identified a novel vertebrate-specific protein complex, shieldin, comprising REV7 plus three previously uncharacterized proteins"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29789392
    review:
      summary: >-
        Interaction with SHLD2/FAM35A demonstrated.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative. Captured by shieldin complex function annotations.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "We identified a novel vertebrate-specific protein complex, shieldin, comprising REV7 plus three previously uncharacterized proteins"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: >-
        Binary protein interactome study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" from high-throughput studies lacks functional context.
      supported_by:
        - reference_id: PMID:20164194
          supporting_text: "REV7 interacts with both REV3 and REV1 polymerases"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32814053
    review:
      summary: >-
        Neurodegenerative disease interactome study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" from high-throughput studies lacks functional context.
      supported_by:
        - reference_id: PMID:20164194
          supporting_text: "REV7 interacts with both REV3 and REV1 polymerases"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        Nucleoplasm localization demonstrated by immunofluorescence.
      action: ACCEPT
      reason: >-
        Nucleoplasm is a more specific localization consistent with REV7's nuclear
        functions in DNA repair.
      supported_by:
        - reference_id: PMID:17541814
          supporting_text: "HCCA2 and MAD2L2 also colocalized in the nucleus of Hela cells"

  - term:
      id: GO:0042276
      label: error-prone translesion synthesis
    evidence_type: IDA
    original_reference_id: PMID:24449906
    review:
      summary: >-
        REV7 as part of Pol zeta participates in error-prone translesion synthesis
        to bypass DNA lesions.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:24449906
          supporting_text: "DNA polymerase zeta (Pol zeta) is a eukaryotic B-family DNA polymerase that specializes in translesion synthesis"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20164194
    review:
      summary: >-
        Crystal structure shows REV7 binding to REV3L and REV1.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative. The specific adapter function is better
        captured by process annotations.
      supported_by:
        - reference_id: PMID:20164194
          supporting_text: "REV7 interacts with both REV3 and REV1 polymerases"

  - term:
      id: GO:0090734
      label: site of DNA damage
    evidence_type: IDA
    original_reference_id: PMID:29656893
    review:
      summary: >-
        REV7 is recruited to sites of DNA damage as part of the shieldin complex.
      action: ACCEPT
      reason: >-
        Localization to DNA damage sites is consistent with REV7's role in the
        shieldin complex for DSB repair.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168-53BP1-RIF1 axis"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23143872
    review:
      summary: >-
        Structural study of translesion polymerase complex assembly.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative. Captured by Pol zeta complex annotations.
      supported_by:
        - reference_id: PMID:20164194
          supporting_text: "we show the first crystal structure of human REV7 in complex with a fragment of human REV3 polymerase"

  - term:
      id: GO:0019985
      label: translesion synthesis
    evidence_type: IDA
    original_reference_id: PMID:20164194
    review:
      summary: >-
        REV7 mediates translesion synthesis as an adapter in the Pol zeta complex.
      action: ACCEPT
      reason: >-
        This is a core function of REV7. The crystal structure and functional studies
        demonstrate REV7's essential role in TLS.
      supported_by:
        - reference_id: PMID:20164194
          supporting_text: "Our results highlight the function of REV7 as an adapter protein to recruit Polzeta to a lesion site"

  - term:
      id: GO:0030674
      label: protein-macromolecule adaptor activity
    evidence_type: IDA
    original_reference_id: PMID:20164194
    review:
      summary: >-
        REV7 functions as an adapter protein bridging REV3L and REV1 in the Pol zeta
        complex.
      action: ACCEPT
      reason: >-
        This accurately captures REV7's molecular function. The HORMA domain mediates
        adapter function through safety-belt mechanism.
      supported_by:
        - reference_id: PMID:20164194
          supporting_text: "Our results highlight the function of REV7 as an adapter protein to recruit Polzeta to a lesion site"

  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:19443654
    review:
      summary: >-
        REV7 negatively regulates TCF4-mediated transcription by preventing DNA binding.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a documented function but represents a secondary pleiotropic effect
        rather than a core molecular function of REV7.
      supported_by:
        - reference_id: PMID:19443654
          supporting_text: "Using the TOPFLASH reporter assay, we found that MAD2B blocks TCF4-mediated transactivation"

  - term:
      id: GO:0003714
      label: transcription corepressor activity
    evidence_type: IMP
    original_reference_id: PMID:19443654
    review:
      summary: >-
        REV7 acts as a transcription corepressor by inhibiting TCF4 DNA binding.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:19443654
          supporting_text: "Using the TOPFLASH reporter assay, we found that MAD2B blocks TCF4-mediated transactivation"

  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: NAS
    original_reference_id: PMID:29656893
    review:
      summary: >-
        REV7 associates with chromatin as part of the shieldin complex at DSB sites.
      action: ACCEPT
      reason: >-
        Chromatin association is consistent with REV7's role in DSB repair as part
        of the shieldin complex.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168-53BP1-RIF1 axis"

  - term:
      id: GO:0002208
      label: somatic diversification of immunoglobulins involved in immune response
    evidence_type: NAS
    original_reference_id: PMID:29656893
    review:
      summary: >-
        REV7 in the shieldin complex promotes immunoglobulin class-switch recombination.
      action: ACCEPT
      reason: >-
        CSR is a physiologically important function of the shieldin complex where
        REV7 is essential.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "promotes NHEJ-dependent repair of intrachromosomal breaks, immunoglobulin class-switch recombination (CSR), and fusion of unprotected telomeres"

  - term:
      id: GO:0035861
      label: site of double-strand break
    evidence_type: NAS
    original_reference_id: PMID:29656893
    review:
      summary: >-
        REV7 is recruited to DSB sites as part of the shieldin complex.
      action: ACCEPT
      reason: >-
        DSB site localization is consistent with shieldin complex function in
        suppressing DNA end resection.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168-53BP1-RIF1 axis"

  - term:
      id: GO:0043247
      label: telomere maintenance in response to DNA damage
    evidence_type: NAS
    original_reference_id: PMID:29656893
    review:
      summary: >-
        REV7 as part of shieldin promotes fusion of unprotected telomeres.
      action: ACCEPT
      reason: >-
        Telomere maintenance is a documented function of the shieldin complex.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "promotes NHEJ-dependent repair of intrachromosomal breaks, immunoglobulin class-switch recombination (CSR), and fusion of unprotected telomeres"

  - term:
      id: GO:2001034
      label: positive regulation of double-strand break repair via nonhomologous end joining
    evidence_type: NAS
    original_reference_id: PMID:29656893
    review:
      summary: >-
        REV7 in shieldin complex promotes NHEJ by suppressing DNA end resection.
      action: ACCEPT
      reason: >-
        This is a core function of REV7 as part of the shieldin complex.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:34354233
    review:
      summary: >-
        Interaction with ASTE1 demonstrated.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative. The ASTE1 interaction relates to
        shieldin function but should be captured by process terms.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "We identified a novel vertebrate-specific protein complex, shieldin, comprising REV7 plus three previously uncharacterized proteins"

  - term:
      id: GO:0005694
      label: chromosome
    evidence_type: IC
    original_reference_id: PMID:29656893
    review:
      summary: >-
        Inferred chromosome localization based on shieldin complex function.
      action: ACCEPT
      reason: >-
        Chromosome localization is consistent with REV7's role in DSB repair.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168-53BP1-RIF1 axis"

  - term:
      id: GO:0035861
      label: site of double-strand break
    evidence_type: IC
    original_reference_id: PMID:29656893
    review:
      summary: >-
        Inferred localization to DSB sites.
      action: ACCEPT
      reason: >-
        Consistent with shieldin complex function and experimental evidence.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168-53BP1-RIF1 axis"

  - term:
      id: GO:0045830
      label: positive regulation of isotype switching
    evidence_type: IDA
    original_reference_id: PMID:29656893
    review:
      summary: >-
        REV7 in shieldin complex is required for immunoglobulin class-switch recombination.
      action: ACCEPT
      reason: >-
        CSR regulation is a documented physiological function of the shieldin complex.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "promotes NHEJ-dependent repair of intrachromosomal breaks, immunoglobulin class-switch recombination (CSR), and fusion of unprotected telomeres"

  - term:
      id: GO:2000042
      label: negative regulation of double-strand break repair via homologous recombination
    evidence_type: IDA
    original_reference_id: PMID:29656893
    review:
      summary: >-
        REV7 in shieldin complex suppresses HR by inhibiting DNA end resection.
      action: ACCEPT
      reason: >-
        This is a core function of REV7. By promoting NHEJ, the shieldin complex
        antagonizes HR.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection"

  - term:
      id: GO:2001034
      label: positive regulation of double-strand break repair via nonhomologous end joining
    evidence_type: IDA
    original_reference_id: PMID:29656893
    review:
      summary: >-
        REV7 in shieldin complex promotes NHEJ.
      action: ACCEPT
      reason: >-
        This is a core function of REV7 as part of the shieldin complex.
      supported_by:
        - reference_id: PMID:29656893
          supporting_text: "Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110311
    review:
      summary: >-
        Reactome pathway annotation for Pol zeta function in nucleoplasm.
      action: ACCEPT
      reason: >-
        Nucleoplasm localization is consistent with TLS and DSB repair functions.
      supported_by:
        - reference_id: PMID:24449906
          supporting_text: "DNA polymerase zeta (Pol zeta) is a eukaryotic B-family DNA polymerase that specializes in translesion synthesis"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-110322
    review:
      summary: >-
        Reactome pathway annotation for Pol zeta complex formation.
      action: ACCEPT
      reason: >-
        Consistent with REV7 function in Pol zeta.
      supported_by:
        - reference_id: PMID:24449906
          supporting_text: "At a minimum, Pol zeta consists of a catalytic subunit Rev3 and an accessory subunit Rev7"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5652151
    review:
      summary: >-
        Reactome annotation for REV1 recruiting Pol zeta.
      action: ACCEPT
      reason: >-
        Consistent with TLS function.
      supported_by:
        - reference_id: PMID:20164194
          supporting_text: "Our results highlight the function of REV7 as an adapter protein to recruit Polzeta to a lesion site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5655835
    review:
      summary: >-
        Reactome annotation for POLK-REV1-POLZ complex.
      action: ACCEPT
      reason: >-
        Consistent with TLS function.
      supported_by:
        - reference_id: PMID:20164194
          supporting_text: "Our results highlight the function of REV7 as an adapter protein to recruit Polzeta to a lesion site"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5655892
    review:
      summary: >-
        Reactome annotation for POLK nucleotide incorporation.
      action: ACCEPT
      reason: >-
        Consistent with TLS pathway.
      supported_by:
        - reference_id: PMID:24449906
          supporting_text: "DNA polymerase zeta (Pol zeta) is a eukaryotic B-family DNA polymerase that specializes in translesion synthesis"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5655965
    review:
      summary: >-
        Reactome annotation for POLK-POLZ cooperation.
      action: ACCEPT
      reason: >-
        Consistent with TLS function.
      supported_by:
        - reference_id: PMID:24449906
          supporting_text: "The purified four-subunit Pol zeta4 (Rev3-Rev7-PolD2-PolD3) is much more efficient and more processive"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5656105
    review:
      summary: >-
        Reactome annotation for POLI binding REV1 and PCNA.
      action: ACCEPT
      reason: >-
        Consistent with TLS pathway.
      supported_by:
        - reference_id: PMID:20164194
          supporting_text: "REV7 interacts with both REV3 and REV1 polymerases"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5656148
    review:
      summary: >-
        Reactome annotation for POLI nucleotide incorporation.
      action: ACCEPT
      reason: >-
        Consistent with TLS pathway.
      supported_by:
        - reference_id: PMID:24449906
          supporting_text: "DNA polymerase zeta (Pol zeta) is a eukaryotic B-family DNA polymerase that specializes in translesion synthesis"

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5656158
    review:
      summary: >-
        Reactome annotation for POLZ elongation of POLI product.
      action: ACCEPT
      reason: >-
        Consistent with TLS function where REV7-containing Pol zeta extends.
      supported_by:
        - reference_id: PMID:24449906
          supporting_text: "The purified four-subunit Pol zeta4 (Rev3-Rev7-PolD2-PolD3) is much more efficient and more processive"

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:19443654
    review:
      summary: >-
        Nuclear localization demonstrated experimentally.
      action: ACCEPT
      reason: >-
        Nuclear localization is well-established for REV7.
      supported_by:
        - reference_id: PMID:17541814
          supporting_text: "HCCA2 and MAD2L2 also colocalized in the nucleus of Hela cells"

  - term:
      id: GO:0007015
      label: actin filament organization
    evidence_type: IMP
    original_reference_id: PMID:19443654
    review:
      summary: >-
        REV7 knockdown affects actin organization as part of EMT phenotype.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is an indirect effect through REV7's modulation of TCF4-mediated
        transcription, not a direct molecular function.
      supported_by:
        - reference_id: PMID:19443654
          supporting_text: "Mesenchymal induction was accompanied by F-actin redistribution and the appearance of a fibroblastoid phenotype"

  - term:
      id: GO:0010719
      label: negative regulation of epithelial to mesenchymal transition
    evidence_type: IMP
    original_reference_id: PMID:19443654
    review:
      summary: >-
        REV7 negatively regulates EMT by modulating TCF4 activity.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a secondary pleiotropic effect through TCF4 interaction.
      supported_by:
        - reference_id: PMID:19443654
          supporting_text: "Knockdown of MAD2B in SW480 colorectal cancer cells led to the conversion of epithelial cells to a mesenchymal fibroblastoid phenotype"

  - term:
      id: GO:0010944
      label: negative regulation of transcription by competitive promoter binding
    evidence_type: IMP
    original_reference_id: PMID:19443654
    review:
      summary: >-
        REV7 binding to TCF4 abolishes TCF4 DNA binding ability.
      action: KEEP_AS_NON_CORE
      reason: >-
        This mechanism explains how REV7 inhibits TCF4 function but is a secondary role.
      supported_by:
        - reference_id: PMID:19443654
          supporting_text: "TCF4 and MAD2B interactions abolished the DNA binding ability of TCF4"

  - term:
      id: GO:0061629
      label: RNA polymerase II-specific DNA-binding transcription factor binding
    evidence_type: IPI
    original_reference_id: PMID:19443654
    review:
      summary: >-
        REV7 binds to TCF4/TCF7L2 transcription factor.
      action: KEEP_AS_NON_CORE
      reason: >-
        This interaction is documented but represents a secondary function.
      supported_by:
        - reference_id: PMID:19443654
          supporting_text: "Thus, MAD2B is a novel TCF4-interacting protein"

  - term:
      id: GO:0090090
      label: negative regulation of canonical Wnt signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:19443654
    review:
      summary: >-
        REV7 inhibits Wnt signaling by blocking TCF4 transcriptional activity.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is an indirect effect through TCF4 inhibition, a secondary function.
      supported_by:
        - reference_id: PMID:19443654
          supporting_text: "Using the TOPFLASH reporter assay, we found that MAD2B blocks TCF4-mediated transactivation"

  - term:
      id: GO:2000048
      label: negative regulation of cell-cell adhesion mediated by cadherin
    evidence_type: IMP
    original_reference_id: PMID:19443654
    review:
      summary: >-
        REV7 knockdown affects E-cadherin expression through TCF4.
      action: KEEP_AS_NON_CORE
      reason: >-
        Indirect effect through TCF4 modulation.
      supported_by:
        - reference_id: PMID:19443654
          supporting_text: "MAD2B knockdown blocked E-cadherin expression"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11717438
    review:
      summary: >-
        Interaction with PRCC demonstrated.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative. PRCC interaction has unclear functional significance.
      supported_by:
        - reference_id: PMID:11717438
          supporting_text: "the mitotic checkpoint protein MAD2B interacts with PRCC"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17541814
    review:
      summary: >-
        Interaction with YY1AP1 demonstrated.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative.
      supported_by:
        - reference_id: PMID:17541814
          supporting_text: "a novel HCCA2-interacting protein, MAD2L2"

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:17541814
    review:
      summary: >-
        Nuclear localization demonstrated.
      action: ACCEPT
      reason: >-
        Consistent with other studies showing nuclear localization.
      supported_by:
        - reference_id: PMID:17541814
          supporting_text: "HCCA2 and MAD2L2 also colocalized in the nucleus of Hela cells"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11459826
    review:
      summary: >-
        Interaction with CDC20 and CDH1/FZR1 demonstrated.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative. The functional consequence (APC inhibition)
        is captured by other annotations.
      supported_by:
        - reference_id: PMID:11459826
          supporting_text: "MAD2B inhibits both CDH1-APC and CDC20-APC. This inhibition is targeted to CDH1 and CDC20"

  - term:
      id: GO:0042177
      label: negative regulation of protein catabolic process
    evidence_type: IDA
    original_reference_id: PMID:11459826
    review:
      summary: >-
        REV7 inhibits APC-mediated protein degradation by binding CDH1/CDC20.
      action: ACCEPT
      reason: >-
        This captures the functional consequence of APC inhibition - prevention of
        ubiquitin-mediated protein degradation.
      supported_by:
        - reference_id: PMID:11459826
          supporting_text: "MAD2B also inhibits APC"
        - reference_id: PMID:11459825
          supporting_text: "MAD2L2 specifically binds and inhibits Cdh1-APC, paralleling the effect of MAD2 on Cdc20"

  - term:
      id: GO:1904667
      label: negative regulation of ubiquitin protein ligase activity
    evidence_type: IDA
    original_reference_id: PMID:11459826
    review:
      summary: >-
        REV7 inhibits APC/C ubiquitin ligase activity through CDH1/CDC20.
      action: ACCEPT
      reason: >-
        This is a core function of REV7 in cell cycle regulation.
      supported_by:
        - reference_id: PMID:11459826
          supporting_text: "MAD2B inhibits both CDH1-APC and CDC20-APC"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17296730
    review:
      summary: >-
        Interaction with ELK1 demonstrated.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative. JNK binding term provides more specificity.
      supported_by:
        - reference_id: PMID:17296730
          supporting_text: "human Rev7 (hRev7)/MAD2B/MAD2L2 as an interaction partner for Elk-1"

  - term:
      id: GO:0005680
      label: anaphase-promoting complex
    evidence_type: IDA
    original_reference_id: PMID:11459825
    review:
      summary: >-
        REV7 colocalizes with the APC through interaction with CDH1.
      action: ACCEPT
      reason: >-
        Physical association with APC is consistent with REV7's role in APC inhibition.
      supported_by:
        - reference_id: PMID:11459825
          supporting_text: "MAD2L2 specifically binds and inhibits Cdh1-APC, paralleling the effect of MAD2 on Cdc20"

  - term:
      id: GO:0008432
      label: JUN kinase binding
    evidence_type: IDA
    original_reference_id: PMID:17296730
    review:
      summary: >-
        REV7 binds JNK kinases to facilitate ELK1 phosphorylation.
      action: KEEP_AS_NON_CORE
      reason: >-
        JNK binding is documented but represents a secondary signaling function.
      supported_by:
        - reference_id: PMID:17296730
          supporting_text: "hRev7 acts to promote Elk-1 phosphorylation by the c-Jun N-terminal protein kinase (JNK) MAP kinases"

  - term:
      id: GO:0033138
      label: positive regulation of peptidyl-serine phosphorylation
    evidence_type: IDA
    original_reference_id: PMID:17296730
    review:
      summary: >-
        REV7 promotes ELK1 serine phosphorylation through JNK pathway.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a secondary signaling function related to DNA damage response.
      supported_by:
        - reference_id: PMID:17296730
          supporting_text: "hRev7 acts to promote Elk-1 phosphorylation"

  - term:
      id: GO:0042772
      label: DNA damage response, signal transduction resulting in transcription
    evidence_type: IDA
    original_reference_id: PMID:17296730
    review:
      summary: >-
        REV7 links DNA damage to transcriptional changes through JNK-ELK1 pathway.
      action: KEEP_AS_NON_CORE
      reason: >-
        While related to DNA damage response, this signaling role is secondary to
        the core TLS and DSB repair functions.
      supported_by:
        - reference_id: PMID:17296730
          supporting_text: "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"

  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IMP
    original_reference_id: PMID:17296730
    review:
      summary: >-
        REV7 promotes transcription through ELK1 activation.
      action: KEEP_AS_NON_CORE
      reason: >-
        Secondary signaling function.
      supported_by:
        - reference_id: PMID:17296730
          supporting_text: "hRev7 therefore contributes to the upregulation of Elk-1 target genes"

  - term:
      id: GO:0001558
      label: regulation of cell growth
    evidence_type: IGI
    original_reference_id: PMID:15988022
    review:
      summary: >-
        REV gene disruption in chicken DT40 cells affects cell growth.
      action: KEEP_AS_NON_CORE
      reason: >-
        Cell growth regulation is an indirect consequence of REV7's roles in
        DNA repair and cell cycle control.
      supported_by:
        - reference_id: PMID:15988022
          supporting_text: "REV1-/- REV3-/- REV7-/- cells showed spontaneous cell death, chromosomal instability/fragility"

  - term:
      id: GO:0006302
      label: double-strand break repair
    evidence_type: IGI
    original_reference_id: PMID:15988022
    review:
      summary: >-
        REV7 participates in DSB repair in vertebrate cells.
      action: ACCEPT
      reason: >-
        DSB repair is a core function of REV7 through the shieldin complex.
      supported_by:
        - reference_id: PMID:15988022
          supporting_text: "REV1-/- REV3-/- REV7-/- cells showed spontaneous cell death, chromosomal instability/fragility"
        - reference_id: PMID:29656893
          supporting_text: "Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection"

  - term:
      id: GO:0016035
      label: zeta DNA polymerase complex
    evidence_type: IDA
    original_reference_id: PMID:20164194
    review:
      summary: >-
        Crystal structure demonstrates REV7 as part of the Pol zeta complex.
      action: ACCEPT
      reason: >-
        This is a core molecular function - REV7 as an essential subunit of Pol zeta.
      supported_by:
        - reference_id: PMID:20164194
          supporting_text: "we show the first crystal structure of human REV7 in complex with a fragment of human REV3 polymerase"

  - term:
      id: GO:0005819
      label: spindle
    evidence_type: IDA
    original_reference_id: PMID:21063390
    review:
      summary: >-
        REV7 localizes to spindle through CHAMP1 interaction.
      action: ACCEPT
      reason: >-
        Spindle localization is consistent with REV7's role in cell cycle regulation.
      supported_by:
        - reference_id: PMID:21063390
          supporting_text: "CAMP localizes to chromosomes and the spindle including kinetochores"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20850016
    review:
      summary: >-
        Interaction with POGZ demonstrated in epigenetic study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative.
      supported_by:
        - reference_id: PMID:20164194
          supporting_text: "REV7 interacts with both REV3 and REV1 polymerases"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11485998
    review:
      summary: >-
        Interaction with REV1 and REV3 demonstrated.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        "Protein binding" is uninformative. The functional consequence (TLS) is
        captured by process annotations.
      supported_by:
        - reference_id: PMID:11485998
          supporting_text: "The interaction between hREV1 and hREV7 was identified by the yeast two-hybrid library screening"

  - term:
      id: GO:0007094
      label: mitotic spindle assembly checkpoint signaling
    evidence_type: TAS
    original_reference_id: PMID:10366450
    review:
      summary: >-
        MAD2L2 was originally identified as a MAD2 homolog with potential checkpoint function.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:10366450
          supporting_text: "we isolated a novel human gene, MAD2B (MAD2L2), which is homologous to the spindle checkpoint gene MAD2"
        - reference_id: PMID:11459826
          supporting_text: "Unlike MAD2, whose interaction with MAD1 is required for mitotic checkpoint control, MAD2B does not interact with MAD1"

  - term:
      id: GO:0110027
      label: negative regulation of DNA strand resection involved in replication fork processing
    evidence_type: IMP
    original_reference_id: PMID:36075897
    review:
      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.
      action: NEW
      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.
      supported_by:
        - reference_id: PMID:36075897
          supporting_text: "this function of MAD2L2 at replication forks is independent of its interaction with shieldin, but instead requires the TLS factors REV3L and REV1"
        - reference_id: PMID:36075897
          supporting_text: "uncontrolled MRE11-dependent resection of stalled forks"

references:
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning models
    findings: []
  - id: PMID:10366450
    title: Characterization of MAD2B and other mitotic spindle checkpoint genes.
    findings:
      - statement: MAD2L2/MAD2B was identified as a novel gene homologous to spindle checkpoint gene MAD2
        supporting_text: "we isolated a novel human gene, MAD2B (MAD2L2), which is homologous to the spindle checkpoint gene MAD2"
  - id: PMID:10527948
    title: Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2beta.
    findings:
      - statement: MAD2beta (MAD2L2) identified as binding partner of MDC9 cytoplasmic domain
        supporting_text: "a novel MAD2-related protein, MAD2beta, as a binding partner of the MDC9 cytoplasmic domain"
  - id: PMID:11459825
    title: "Inhibition of Cdh1-APC by the MAD2-related protein MAD2L2: a novel mechanism for regulating Cdh1."
    findings:
      - statement: MAD2L2 specifically binds and inhibits Cdh1-APC
        supporting_text: "MAD2L2 specifically binds and inhibits Cdh1-APC, paralleling the effect of MAD2 on Cdc20"
  - id: PMID:11459826
    title: MAD2B is an inhibitor of the anaphase-promoting complex.
    findings:
      - statement: MAD2B inhibits both CDH1-APC and CDC20-APC
        supporting_text: "MAD2B also inhibits APC. In contrast to MAD2, MAD2B inhibits both CDH1-APC and CDC20-APC"
      - statement: Unlike MAD2, MAD2B does not interact with MAD1
        supporting_text: "Unlike MAD2, whose interaction with MAD1 is required for mitotic checkpoint control, MAD2B does not interact with MAD1"
  - id: PMID:11485998
    title: Interactions in the error-prone postreplication repair proteins hREV1, hREV3, and hREV7.
    findings:
      - statement: hREV7 interacts with both hREV1 and hREV3
        supporting_text: "The interaction between hREV1 and hREV7 was identified by the yeast two-hybrid library screening"
      - statement: hREV7 homodimerizes
        supporting_text: "The homodimerization of hREV7 was also detected in the two-hybrid analysis"
  - id: PMID:15988022
    title: Multiple roles of vertebrate REV genes in DNA repair and recombination.
    findings:
      - statement: REV7 knockout cells show chromosomal instability and hypersensitivity to genotoxic agents
        supporting_text: "REV1-/- REV3-/- REV7-/- cells showed spontaneous cell death, chromosomal instability/fragility"
  - id: PMID:17296730
    title: Rev7/MAD2B links c-Jun N-terminal protein kinase pathway signaling to activation of the transcription factor Elk-1.
    findings:
      - statement: hRev7 promotes Elk-1 phosphorylation by JNK kinases
        supporting_text: "hRev7 acts to promote Elk-1 phosphorylation by the c-Jun N-terminal protein kinase (JNK) MAP kinases"
  - id: PMID:19443654
    title: MAD2B, a novel TCF4-binding protein, modulates TCF4-mediated epithelial-mesenchymal transdifferentiation.
    findings:
      - statement: MAD2B interacts with TCF4 and blocks its transactivation
        supporting_text: "Using the TOPFLASH reporter assay, we found that MAD2B blocks TCF4-mediated transactivation"
      - statement: MAD2B knockdown induces EMT
        supporting_text: "Knockdown of MAD2B in SW480 colorectal cancer cells led to the conversion of epithelial cells to a mesenchymal fibroblastoid phenotype"
  - id: PMID:20164194
    title: Crystal structure of human REV7 in complex with a human REV3 fragment and structural implication of the interaction between DNA polymerase zeta and REV1.
    findings:
      - statement: REV7 functions as adapter protein to recruit Pol zeta to lesion sites
        supporting_text: "Our results highlight the function of REV7 as an adapter protein to recruit Polzeta to a lesion site"
      - statement: Crystal structure reveals REV7-REV3 interaction mechanism
        supporting_text: "we show the first crystal structure of human REV7 in complex with a fragment of human REV3 polymerase"
  - id: PMID:21063390
    title: CAMP (C13orf8, ZNF828) is a novel regulator of kinetochore-microtubule attachment.
    findings:
      - statement: REV7/MAD2L2 interacts with CHAMP1
        supporting_text: "CAMP localizes to chromosomes and the spindle including kinetochores"
  - id: PMID:24449906
    title: Human Pol ζ purified with accessory subunits is active in translesion DNA synthesis and complements Pol η in cisplatin bypass.
    findings:
      - statement: Pol zeta4 (Rev3-Rev7-PolD2-PolD3) is the fully active form
        supporting_text: "The purified four-subunit Pol zeta4 (Rev3-Rev7-PolD2-PolD3) is much more efficient and more processive"
      - statement: Complete bypass of cisplatin lesions requires Pol eta insertion and Pol zeta4 extension
        supporting_text: "complete bypass of cisplatin lesions requires Pol eta to insert dCTP opposite the 3' guanine and Pol zeta4 to extend the primers"
  - id: PMID:29656893
    title: DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity.
    findings:
      - statement: Shieldin complex comprises REV7 plus SHLD1, SHLD2, SHLD3
        supporting_text: "We identified a novel vertebrate-specific protein complex, shieldin, comprising REV7 plus three previously uncharacterized proteins"
      - statement: Shieldin promotes NHEJ by restraining DNA end resection
        supporting_text: "Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection"
      - statement: Shieldin mediates CSR and telomere fusion
        supporting_text: "promotes NHEJ-dependent repair of intrachromosomal breaks, immunoglobulin class-switch recombination (CSR), and fusion of unprotected telomeres"
  - id: PMID:29789392
    title: FAM35A associates with REV7 and modulates DNA damage responses of normal and BRCA1-defective cells.
    findings:
      - statement: FAM35A/SHLD2 associates with REV7
        supporting_text: "FAM35A associates with REV7"
  - id: PMID:34354233
    title: ASTE1 promotes shieldin-complex-mediated DNA repair by attenuating end resection.
    findings:
      - statement: ASTE1 interacts with REV7 to promote shieldin function
        supporting_text: "ASTE1 promotes shieldin-complex-mediated DNA repair"
  - id: PMID:10531379
    title: Interaction of the metalloprotease disintegrins MDC9 and MDC15 with two SH3 domain-containing proteins, endophilin I and SH3PX1.
    findings: []
  - id: PMID:11277934
    title: Trichosanthin interacts with acidic ribosomal proteins P0 and P1 and mitotic checkpoint protein MAD2B.
    findings: []
  - id: PMID:11717438
    title: Impairment of MAD2B-PRCC interaction in mitotic checkpoint defective t(X;1)-positive renal cell carcinomas.
    findings:
      - statement: MAD2B interacts with PRCC
        supporting_text: "the mitotic checkpoint protein MAD2B interacts with PRCC"
  - id: PMID:17541814
    title: Hepatocellular carcinoma-associated gene 2 interacts with MAD2L2.
    findings:
      - statement: HCCA2 interacts with MAD2L2 and they colocalize in the nucleus
        supporting_text: "HCCA2 and MAD2L2 also colocalized in the nucleus of Hela cells"
  - id: PMID:17719540
    title: A bacterial effector targets Mad2L2, an APC inhibitor, to modulate host cell cycling.
    findings:
      - statement: Shigella IpaB targets Mad2L2 to cause cell cycle arrest
        supporting_text: "the Shigella effector IpaB, when delivered into epithelial cells, causes cell-cycle arrest by targeting Mad2L2"
  - id: PMID:20850016
    title: Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers.
    findings: []
  - id: PMID:22828282
    title: The C-terminal domain of human Rev1 contains independent binding sites for DNA polymerase η and Rev7 subunit of polymerase ζ.
    findings: []
  - id: PMID:23143872
    title: Structural insights into the assembly of human translesion polymerase complexes.
    findings: []
  - id: PMID:25416956
    title: A proteome-scale map of the human interactome network.
    findings: []
  - id: PMID:26496610
    title: "A human interactome in three quantitative dimensions organized by stoichiometries and abundances."
    findings: []
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings: []
  - id: PMID:32814053
    title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
    findings: []
  - id: Reactome:R-HSA-110311
    title: Translesion synthesis
    findings: []
  - id: Reactome:R-HSA-110322
    title: Formation of Pol zeta complex
    findings: []
  - id: Reactome:R-HSA-5652151
    title: REV1 recruits POLZ to damaged DNA
    findings: []
  - id: Reactome:R-HSA-5655835
    title: POLK forms quaternary complex with REV1 and POLZ
    findings: []
  - id: Reactome:R-HSA-5655892
    title: POLK incorporates dNMP opposite damaged DNA
    findings: []
  - id: Reactome:R-HSA-5655965
    title: POLK and POLZ cooperate in elongation
    findings: []
  - id: Reactome:R-HSA-5656105
    title: POLI binds REV1 and monoUb-PCNA
    findings: []
  - id: Reactome:R-HSA-5656148
    title: POLI incorporates dNMP
    findings: []
  - id: Reactome:R-HSA-5656158
    title: POLZ elongates POLI product
    findings: []
  - id: PMID:27500492
    title: Biallelic inactivation of REV7 is associated with Fanconi anemia.
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: >-
        PubMed-verified (Bluteau et al., J Clin Invest 2016; abstract-only in cache). Identifies
        REV7/MAD2L2 as Fanconi anemia gene FANCV via biallelic inactivating mutations (REV7-V85E),
        with patient cells showing an extended FA phenotype rescued by WT REV7. Provides the disease
        basis for the FANCV statement in the description; cited on the GO:0006281 DNA repair annotation.
    findings:
      - statement: REV7/MAD2L2 is Fanconi anemia complementation group gene FANCV
        supporting_text: "identified REV7 as a previously undescribed FA gene, which we term FANCV"
  - id: PMID:36075897
    title: MAD2L2 promotes replication fork protection and recovery in a shieldin-independent and REV3L-dependent manner.
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: >-
        PubMed-verified (Paniagua et al., Nat Commun 2022; full text in cache). Establishes a
        shieldin-independent, REV3L/REV1-dependent role for MAD2L2 in protecting and restarting
        stalled replication forks by limiting MRE11-mediated resection of nascent DNA. Supports the
        new GO:0110027 annotation; a function absent from GOA and previously uncaptured in the review.
    findings:
      - statement: MAD2L2 protects stalled replication forks from MRE11-dependent resection, independently of shieldin and dependent on REV3L/REV1
        supporting_text: "MAD2L2 is essential for the protection of stalled replication forks and their efficient restart after replication stress"
  - id: file:human/MAD2L2/MAD2L2-deep-research-falcon.md
    title: Deep research on MAD2L2
    findings:
      - statement: REV7 dimerization is required for TLS and shieldin functions
        supporting_text: "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"

proposed_new_terms: []

suggested_questions:
  - question: How is REV7 partitioned between its roles in Pol zeta versus the shieldin complex?
  - question: What determines whether REV7 functions in TLS versus DSB repair pathway choice?
  - question: How does TRIP13/p31comet regulate REV7 complex disassembly?

suggested_experiments:
  - description: 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
  - description: Live-cell imaging to track REV7 dynamics at DNA damage sites
    hypothesis: REV7 shows distinct recruitment kinetics to replication-associated versus DSB damage
  - description: Characterization of REV7 post-translational modifications that regulate complex assembly
    hypothesis: Specific PTMs control whether REV7 assembles with Pol zeta or shieldin components