Affinage

MAD2L2

Mitotic spindle assembly checkpoint protein MAD2B · UniProt Q9UI95

Length
211 aa
Mass
24.3 kDa
Annotated
2026-04-28
100 papers in source corpus 46 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAD2L2 (REV7) is a HORMA-domain adaptor protein that functions as a central hub in DNA damage tolerance, DNA double-strand break repair pathway choice, and cell cycle regulation. As the non-catalytic subunit of DNA polymerase zeta, MAD2L2 homodimerizes on two REV7-binding motifs in REV3L and bridges REV1 to Pol zeta at stalled replication forks, enabling translesion synthesis past UV- and crosslink-induced lesions; this function is essential for replication fork protection and restart independently of its role in DSB repair, and biallelic loss-of-function mutations cause Fanconi anemia (complementation group FANCV) (PMID:25567983, PMID:30111544, PMID:36075897, PMID:27500492). As the core subunit of the shieldin complex (SHLD1–SHLD2–SHLD3–REV7), MAD2L2 is recruited to DSBs through the 53BP1–RIF1 axis, where it blocks 5′ end resection to promote NHEJ and immunoglobulin class-switch recombination; this activity is antagonized by the TRIP13 ATPase (assisted by p31comet), which converts MAD2L2 from a closed to an open HORMA conformation, dissociating shieldin and enabling BRCA1-dependent homologous recombination (PMID:25799990, PMID:30046110, PMID:31915374, PMID:33051298). MAD2L2 additionally inhibits both CDH1-APC/C and CDC20-APC/C to regulate mitotic progression, and contributes to primordial germ cell maintenance through epigenetic programming involving G9a/GLP and CDK1 inhibition (PMID:11459825, PMID:11459826, PMID:24009519).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1985 High

    The founding question — whether a dedicated gene existed for damage-induced mutagenesis beyond the RAD6 pathway — was answered by identifying yeast REV7 as essential for UV mutagenesis within the RAD6 epistasis group, establishing the gene's role in replication bypass of DNA lesions.

    Evidence Genetic epistasis analysis and UV mutagenesis assays in S. cerevisiae

    PMID:3897794

    Open questions at the time
    • No protein product characterized
    • Mechanism of action in mutagenesis unknown
    • No mammalian ortholog identified
  2. 2000 Medium

    How human REV7 connects to the translesion synthesis machinery was clarified by demonstrating that MAD2L2 directly interacts with REV3L (Pol zeta catalytic subunit), establishing it as an accessory subunit of Pol zeta in humans.

    Evidence Yeast two-hybrid screen and interaction domain mapping

    PMID:10660610

    Open questions at the time
    • Interaction not confirmed with purified proteins
    • Enzymatic contribution of REV7 to Pol zeta activity unknown
  3. 2001 High

    A second major function was uncovered when MAD2L2 was shown to inhibit both CDH1-APC/C and CDC20-APC/C in vitro, revealing an unexpected role in cell cycle regulation distinct from its TLS function and from MAD2's exclusive CDC20 inhibition.

    Evidence In vitro APC ubiquitination assays and co-immunoprecipitation, confirmed by two independent groups

    PMID:11459825 PMID:11459826

    Open questions at the time
    • Physiological relevance of APC inhibition in vivo not demonstrated
    • Signal that activates MAD2L2-dependent APC inhibition unknown
  4. 2003 High

    Whether REV7 directly modulates REV1 catalytic activity was resolved: human REV7 and REV1 form a stable heterodimer, but REV7 does not alter REV1 enzymatic parameters, positioning REV7 as a structural adaptor rather than an enzymatic regulator.

    Evidence Purified recombinant complex characterization, gel filtration, and kinetic analysis

    PMID:12529368

    Open questions at the time
    • Full Pol zeta holoenzyme not reconstituted
    • How REV7 bridges REV1 and REV3 structurally unresolved
  5. 2010 High

    The structural basis for REV7's adaptor function was established: crystal structures of REV7–REV3 and the ternary Rev1-CTD–REV7–REV3 complex revealed that REV7 uses its safety-belt region to capture REV3 peptides while presenting an independent β-sheet surface for REV1 binding, explaining how it bridges two TLS components.

    Evidence X-ray crystallography with mutagenesis and in vitro binding validation

    PMID:20164194 PMID:22859296

    Open questions at the time
    • No structure of full-length Pol zeta holoenzyme
    • Conformational dynamics of REV7 in vivo unknown
  6. 2013 High

    A developmental requirement for MAD2L2 was revealed: Mad2l2-knockout mice lose primordial germ cells through apoptosis, with REV7 interacting with H3K9 methyltransferases G9a/GLP and inhibiting CDK1 to enable epigenetic reprogramming during PGC specification.

    Evidence Knockout mouse model with co-IP, immunofluorescence, and cell cycle analysis

    PMID:23463509 PMID:24009519

    Open questions at the time
    • Whether PGC loss reflects TLS deficiency, APC regulation, or epigenetic function is not fully disentangled
    • Direct chromatin substrates of the REV7-G9a/GLP interaction unknown
  7. 2015 High

    A third major function was discovered: MAD2L2 accumulates at DSBs downstream of 53BP1–RIF1 and blocks 5′ end resection to promote NHEJ; its loss in BRCA1-deficient cells restores HR and causes PARP inhibitor resistance, establishing REV7 as a key determinant of DSB repair pathway choice.

    Evidence Functional genetic screens, telomere FISH, resection assays, CSR assays, epistasis analysis, and PARP inhibitor resistance assays in two independent studies

    PMID:25799990 PMID:25799992

    Open questions at the time
    • Downstream effectors of REV7-mediated end protection unknown
    • Whether REV7 acts alone or in a complex at DSBs unresolved
  8. 2016 High

    The clinical relevance of REV7's DNA repair function was established when biallelic MAD2L2 mutations were identified as a cause of Fanconi anemia (FANCV), with CRISPR knockout phenocopying the crosslinker sensitivity and chromosomal breakage.

    Evidence Patient-derived cells, CRISPR/Cas9 KO, wild-type rescue, chromosomal breakage assays

    PMID:27500492

    Open questions at the time
    • Genotype-phenotype spectrum not fully defined
    • Whether all FA features stem from TLS deficiency or also from NHEJ defects unclear
  9. 2018 High

    The downstream effector complex was identified: REV7 is the core of the shieldin complex (SHLD1–SHLD2–SHLD3–REV7), which executes 53BP1-dependent end protection; REV7 homodimerization driven by two REV3-binding-motif-like sequences in SHLD2 is required for shieldin assembly and NHEJ.

    Evidence Mass spectrometry interactomics, co-IP, CSR assays, DNA end resection assays from multiple independent laboratories; in vitro binding and cell-based complementation with dimer-interface mutants

    PMID:29789392 PMID:30046110 PMID:30111544 PMID:30154076

    Open questions at the time
    • Structure of complete shieldin complex not determined
    • How shieldin physically blocks nuclease access at DNA ends unknown
  10. 2020 High

    How REV7's HORMA domain is regulated was resolved: TRIP13 ATPase, assisted by p31comet, catalyzes a closed-to-open conformational switch in REV7 that disassembles both the shieldin and Pol zeta complexes, providing a unified inactivation mechanism controlling both NHEJ and TLS.

    Evidence Reconstituted conformational change assay, co-IP, TLS and PARP inhibitor resistance assays

    PMID:31915374 PMID:33051298

    Open questions at the time
    • Spatial and temporal regulation of TRIP13 activity at DSBs versus replication forks not delineated
    • Whether additional HORMA regulators exist for REV7 is unknown
  11. 2022 High

    REV7's functions at replication forks versus DSBs were genetically separated: MAD2L2 cooperates with REV3L and REV1 (but not shieldin subunits) to protect and restart stalled forks by preventing MRE11-dependent resection, while CHAMP1 competes with SHLD3 for REV7's seatbelt domain to antagonize shieldin and promote HR.

    Evidence Single-molecule DNA fiber assays with genetic epistasis; competition binding assays with HR and resection readouts

    PMID:36044844 PMID:36075897

    Open questions at the time
    • Mechanism by which Pol zeta protects forks structurally unresolved
    • Regulation of CHAMP1–REV7 versus SHLD3–REV7 competition in vivo unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: how shieldin physically blocks nuclease access at resected DNA ends; the full structural architecture of the shieldin complex; and how the competing demands on REV7 from TLS, NHEJ, APC inhibition, and fork protection are coordinated during the cell cycle.
  • No cryo-EM or crystal structure of assembled shieldin on DNA
  • Cell-cycle-dependent partitioning of REV7 among its distinct complexes not quantified
  • In vivo relevance of REV7-mediated APC/C inhibition remains unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 7 GO:0098772 molecular function regulator activity 4 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005694 chromosome 5 GO:0005634 nucleus 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-73894 DNA Repair 6 R-HSA-1640170 Cell Cycle 3 R-HSA-168256 Immune System 3 R-HSA-1643685 Disease 1
Partners
CDH1RANREV1REV3LSHLD1SHLD2SHLD3TRIP13
Complex memberships
DNA polymerase zeta (REV3L-REV7)REV1-REV7 heterodimerShieldin (SHLD1-SHLD2-SHLD3-REV7)

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1985 REV7 (yeast ortholog of MAD2L2) is required for UV-induced mutagenesis in S. cerevisiae and belongs to the RAD6 epistasis group, establishing its role in damage-induced replication bypass. Genetic screen, UV mutagenesis assays, epistasis analysis Molecular & general genetics High 3897794
1994 Yeast REV7 encodes a 28.7 kDa protein required for DNA damage-induced mutagenesis; cloned by complementation of rev7-2 mutant defect, establishing its role in promoting replication past DNA lesions. Complementation cloning, sequence analysis Yeast High 7871890
1999 MAD2L2 (MAD2B) was identified as a novel human gene homologous to spindle checkpoint gene MAD2 (MAD2L1); chromosomally localized to a region implicated in cancer but no mutations found in aneuploid colorectal tumors. Sequence homology, chromosomal localization, mutational screening Genomics Medium 10366450
2000 Human REV7 (hREV7/MAD2L2) interacts with hREV3 (DNA polymerase zeta catalytic subunit) via a defined interaction domain; also interacts with hMAD2 but not hMAD1, suggesting a role as adaptor in human DNA polymerase zeta complex. Yeast two-hybrid screen, interaction domain mapping The Journal of biological chemistry Medium 10660610
2001 MAD2L2 specifically binds and inhibits Cdh1-APC (anaphase-promoting complex), paralleling the inhibition of Cdc20-APC by MAD2; this represents a novel mechanism for regulating Cdh1. In vitro APC ubiquitination assay, binding assay Genes & development High 11459825 11459826
2001 MAD2B (MAD2L2) inhibits both CDH1-APC and CDC20-APC by targeting CDH1 and CDC20, distinguishing it from MAD2 which only inhibits CDC20-APC; MAD2B does not interact with MAD1, suggesting it relays a different signal to APC. In vitro APC ubiquitination assay, co-immunoprecipitation Genes & development High 11459826
2001 MAD2B interacts with PRCC (papillary renal cell carcinoma protein), and the PRCCTFE3 fusion protein retains the MAD2B interaction domain but impairs this interaction, leading to mitotic checkpoint defects. Co-immunoprecipitation, transfection, mitotic checkpoint assay PNAS Medium 11717438
2003 Human REV1 and REV7 form a stable heterodimer in solution; however, REV7 does not influence the stability, substrate specificity, or kinetic parameters of REV1 transferase activity, differing from yeast where Rev7 stimulates Rev3 polymerase. Protein purification, biochemical transferase assay, gel filtration The Journal of biological chemistry High 12529368
2005 In yeast, Rev1 forms a stable complex with Rev7, co-purifying together; the polymerase-associated domain (PAD) of Rev1 mediates its binding to Rev7, revealing a novel role for the PAD in protein-protein interactions. Co-purification, pull-down assay, domain mapping Molecular and cellular biology High 16227619
2007 Shigella effector IpaB interacts with Mad2L2 in epithelial cells, causing unscheduled APC activation and cell-cycle arrest at G2/M; IpaB/Mad2L2-dependent arrest facilitates bacterial colonization. Co-immunoprecipitation, cyclin B1 ubiquitination assay, synchronized cell infection, rabbit intestinal model Cell High 17719540
2007 Human Rev7/MAD2B interacts with transcription factor Elk-1 and promotes Elk-1 phosphorylation by JNK MAP kinases, thereby upregulating Elk-1 target genes (e.g., egr-1) in response to DNA-damaging stress. Co-immunoprecipitation, kinase assay, reporter gene assay Molecular and cellular biology Medium 17296730
2009 MAD2B interacts with TCF4, blocking TCF4-mediated transactivation and DNA binding; MAD2B knockdown in colorectal cancer cells induces epithelial-mesenchymal transdifferentiation with loss of E-cadherin and induction of Slug via TCF4. Co-immunoprecipitation, EMSA, TOPFLASH reporter assay, ChIP, siRNA knockdown The Journal of biological chemistry Medium 19443654
2009 MAD2B interacts with small GTPase RAN throughout the cell cycle; interaction maps to C-terminal 60 amino acids of RAN and requires full-length MAD2B; co-localization at the mitotic spindle is observed. Co-immunoprecipitation, confocal microscopy, domain mapping PloS one Medium 19753112
2010 Crystal structure of human REV7 in complex with a REV3 fragment (residues 1847-1898) reveals the structural basis of REV7-REV3 interaction and shows that this interface also serves for REV1 binding, establishing REV7 as an adaptor protein recruiting Pol zeta to lesion sites. X-ray crystallography, in vitro binding assays, mutagenesis, cellular complementation The Journal of biological chemistry High 20164194
2010 MAD2B interacts with clathrin light chain A (CLTA) during G2/M phase; they co-localize at the mitotic spindle; MAD2B depletion redistributes CLTA away from the spindle and increases misaligned chromosomes. Co-immunoprecipitation, GST pull-down, confocal microscopy, siRNA knockdown PloS one Medium 21152103
2010 REV7 and MAD2 share overlapping short sequence motifs for binding partners; a REV3 sequence is sufficient for binding hREV7 and is also bound by hMAD2, while adapter specificity is maintained for other partners (ADAM9, ELK-1 for REV7; MAD1/CDC20 for MAD2). Binding assays, peptide competition, co-immunoprecipitation Genes to cells Medium 20088965
2012 Crystal structure of the ternary complex of Rev1 C-terminal domain, REV7, and a REV3 fragment reveals that Rev1 CTD uses a four-helix bundle with a conserved linker to contact the REV7 β-sheet, providing the structural basis for Pol zeta recruitment to stalled replication forks; the Rev1 binding site on REV7 is distinct from that of Pol eta/kappa. X-ray crystallography, in vitro binding assays The Journal of biological chemistry High 22859296
2012 REV7 is required for APC/C-dependent ubiquitination and proteasomal degradation of REV1; CDH1 or CDC20 overexpression promotes REV1 polyubiquitination and degradation, and this requires REV7; REV7 depletion stabilizes REV1 by preventing polyubiquitination. Co-immunoprecipitation, polyubiquitination assay, proteasome inhibition, siRNA knockdown Cell cycle Medium 23287467
2012 NMR spectroscopy demonstrates that the Rev1 C-terminal domain simultaneously binds pol eta and REV7 (subunit of pol zeta) through independent interaction interfaces, establishing it as a scaffold for multiple TLS polymerases. NMR spectroscopy, binding assays FEBS letters High 22828282
2013 REV7 (Mad2l2) is essential for primordial germ cell maintenance in mice; Mad2l2-/- mice are infertile due to progressive loss of PGCs by apoptosis during migration; Mad2l2 interacts with histone methyltransferases G9a and GLP to downregulate H3K9me2, and inhibits CDK1 to arrest cells in G2, allowing Ezh2 to upregulate H3K27me3. Knockout mouse, co-immunoprecipitation, immunofluorescence, cell cycle analysis, apoptosis assay PLoS genetics High 24009519
2013 In REV7-deficient mice, loss of REV7 causes primordial germ cell depletion, growth retardation, and partial embryonic lethality; mutant REV7-C70R fails to interact with REV3, disrupting Pol zeta and impairing DNA damage tolerance during S phase. Missense mutant mouse, positional cloning, transgenic rescue, co-immunoprecipitation, gamma-H2AX assay The Journal of biological chemistry High 23463509 24356953
2015 REV7 interacts with full-length REV3L in vivo via two REV7-binding sites (residues 1877-1887 and 1993-2003); mutation of both sites eliminates REV7-REV3L interaction; both sites are necessary to prevent spontaneous chromosome breaks and confer UV and cisplatin resistance, demonstrating that REV7's damage tolerance function is specifically linked to Pol zeta. Co-immunoprecipitation, in vivo complementation, site-directed mutagenesis, chromosome break assay Nucleic acids research High 25567983
2015 MAD2L2 accumulates at uncapped telomeres and irradiation-induced DSBs, inhibits 5' end resection, and promotes NHEJ-mediated chromosome end fusions and class switch recombination; these activities depend on ATM, RNF8, RNF168, 53BP1, and RIF1 but not on PTIP, REV1, or REV3. Functional genetic screen, siRNA knockdown, telomere FISH, gamma-H2AX foci, resection assay, class switch recombination assay, epistasis Nature High 25799990
2015 Loss of REV7 (MAD2L2) in BRCA1-deficient cells re-establishes CTIP-dependent DSB end resection, restoring HR and causing PARP inhibitor resistance; REV7 is recruited to DSBs via the H2AX-MDC1-RNF8-RNF168-53BP1 pathway and blocks DSB resection to promote NHEJ; ATM inhibition reverses this resistance. siRNA knockdown, HR assay, PARP inhibitor resistance assay, chromatin recruitment assay, epistasis Nature High 25799992
2015 Rev7/Mad2B is required for functional mitotic spindle assembly; Rev7 depletion leads to G2/M arrest, monoastral and abnormal spindles, misaligned chromosomes, and Mad2 accumulation at kinetochores; Rev7 interacts physically with RAN GTPase, likely mediating its spindle role. siRNA knockdown, live cell imaging, co-immunoprecipitation, spindle morphology analysis Cell cycle Medium 26697843
2016 Biallelic inactivating mutations of REV7 cause a Fanconi anemia phenotype (increased chromosome breaks, G2/M accumulation, γH2AX foci upon crosslinking agent exposure); wild-type REV7 rescue restores normal phenotype; CRISPR KO of REV7 in normal cells phenocopies FA, identifying REV7 as FANCV. Patient-derived cells, CRISPR/Cas9 KO, rescue experiment, crosslinker sensitivity, chromosomal breakage assay The Journal of clinical investigation High 27500492
2017 Crystal structures of MAD2L2 in complex with the CAMP (chromosome alignment-maintaining phosphoprotein) fragment reveal a novel WK motif in CAMP that binds MAD2L2 differently from REV3; one crystal form shows a MAD2L2 dimer with C-terminal swapping, providing evidence for dynamic MAD2L2 structure relevant to its multifunctionality. X-ray crystallography, structure-based interaction analysis The Journal of biological chemistry High 28887307
2017 Rev7 undergoes ubiquitin/proteasome-mediated degradation upon UV irradiation in a time-dependent manner; Cul4A/B are the putative E3 ligases; the Rev7 N-terminal destruction box serves as the degron; HR23B physically interacts with Rev7 and protects it from accelerated degradation. Protein degradation assay, domain mutagenesis, co-immunoprecipitation, colocalization, siRNA knockdown The FEBS journal Medium 28440919
2018 H4K20me2 in pre-replicative chromatin drives robust 53BP1-RIF1-MAD2L2 complex recruitment at DSBs, directing NHEJ; replication-associated dilution of H4K20me2 releases this complex, allowing BRCA1-driven HR, providing an epigenetic mechanism for replication-status-dependent repair pathway choice. Chromatin fractionation, co-immunoprecipitation, fluorescence microscopy, cell cycle analysis Cell cycle Medium 29160738
2018 REV7 is the core component of the shieldin complex (REV7-SHLD1-SHLD2-SHLD3); shieldin is required for REV7-dependent DNA end-protection and NHEJ during class switch recombination; SHLD2 has OB-fold domains similar to RPA and accumulates at DSBs in a 53BP1-RIF1-REV7-dependent manner. Mass spectrometry interactome, siRNA knockdown, co-immunoprecipitation, class switch recombination assay, DNA end resection assay Nature High 29789392 30046110 30154076
2018 Rev7 dimerization through the canonical HORMA interface is required for TLS complex assembly; when tethered by two RBMs in Rev3, Rev7 forms a homodimer that can bind only one copy of Rev1; mutation of the Rev7 dimer interface increases cellular DNA damage sensitivity. In vitro binding assays, structural analysis, cell-based complementation in Rev7-/- cells, mutagenesis PNAS High 30111544
2018 MAD2L2 promotes colorectal cancer suppression by interacting with NCOA3 and inducing its ubiquitination and proteasomal degradation via p38 kinase-dependent phosphorylation of NCOA3. Co-immunoprecipitation, mass spectrometry, ubiquitination assay, western blot Molecular oncology Medium 29360267
2019 Crystal structures of REV7 in complex with RAN and Shigella IpaB fragments reveal that both bind the safety-belt region of REV7, inducing C-terminal β-sheet rearrangement; REV7 preferentially binds GTP-bound RAN, suggesting that the RAN GTP/GDP switch regulates REV7 activity. X-ray crystallography, biochemical binding assay The Journal of biological chemistry High 31484720
2019 Crystal structures of REV7 in complex with SHLD3's REV7-binding domain reveal that the SHLD3 ladle-shaped RBD uses both an N-terminal loop and C-terminal αC-helix to bind REV7, with the REV7 safety-belt region essential for high-affinity (low-nM) SHLD3 binding. X-ray crystallography, in vitro and in vivo binding assays, binding kinetics The Journal of biological chemistry High 31796627
2019 REV7 interacts with PRDX2 (peroxiredoxin 2); this complex is augmented after irradiation and assembles onto DNA DSBs; REV7 knockdown disrupts nuclear PRDX2 localization post-irradiation, increasing reactive oxygen species and DSBs. Co-immunoprecipitation, mass spectrometry, immunofluorescence, xenograft Cancer science Medium 30657231
2020 TRIP13 ATPase catalyzes an inactivating conformational change in REV7 from 'closed' (active) to 'open' (inactive), dissociating REV7-Shieldin and promoting HR; TRIP13 similarly disassembles the REV7-REV3 TLS complex, inhibiting TLS. Biochemical conformational assay, co-immunoprecipitation, TLS assay, PARP inhibitor resistance assay Nature cell biology High 31915374
2020 p31comet binds to the REV7-Shieldin complex and promotes REV7 inactivation through the TRIP13 ATPase, causing SHLD3 dissociation and PARP inhibitor resistance; p31comet also counteracts REV7 function in TLS by releasing REV7 from REV3. Co-immunoprecipitation, chromatin fractionation, PARP inhibitor resistance assay, TLS assay PNAS High 33051298
2020 REV7-dependent TLS across UNG-processed apurinic/apyrimidinic sites is required for B cell survival upon AID/APOBEC deamination, independent of REV7's roles in DSBR, G2/M transition, or REV1-mediated TLS. Conditional KO mouse, epistasis with AID-deficiency, survival assay, TLS assay Nature communications High 32499490
2021 MAD2L2 dimerization, mediated by SHLD2 and accelerating MAD2L2-SHLD3 interaction, is required for proper shieldin complex assembly and NHEJ activity; dimerization-defective MAD2L2 impairs shieldin assembly and NHEJ; TRIP13 interaction with shieldin requires MAD2L2 dimerization plus SHLD3 presence. Co-immunoprecipitation, NHEJ assay, mutagenesis, biochemical interaction assays Nature communications High 34521823
2020 CDH1 interacts with MAD2L2 using the same C-terminus interface on MAD2L2 that REV1 uses (Rev1-like pattern); the C-terminus of MAD2L2 is also essential for homodimerization. Mutagenesis, co-immunoprecipitation in human cell line Biochemical and biophysical research communications Medium 32811646
2022 MAD2L2 is required for protecting and restarting stalled replication forks independently of shieldin; MAD2L2 loss leads to uncontrolled MRE11-dependent resection and ssDNA accumulation; MAD2L2 cooperates with REV3L and REV1 (but not shieldin subunits) to promote fork stability. Genetic KO, single-molecule DNA fiber assay, siRNA epistasis, ssDNA accumulation assay Nature communications High 36075897
2022 CHAMP1 binds directly to REV7 via its seatbelt domain (competing with SHLD3) and reduces Shieldin complex levels, increasing DSB end resection and promoting HR; CHAMP1 also interacts with POGZ in a heterochromatin complex to further promote HR. Co-immunoprecipitation, DNA end resection assay, HR assay, competition binding assay Cell reports High 36044844
2024 REV7 directly binds p53 and blocks ATM-dependent phosphorylation of p53 at Ser15; REV7 is also involved in destabilization of p53. Co-immunoprecipitation, phosphorylation assay, western blot Cell cycle Medium 38557443

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature 498 25799992
2018 53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ. Nature 252 30046110
2015 MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5' end resection. Nature 249 25799990
1999 Characterization of MAD2B and other mitotic spindle checkpoint genes. Genomics 185 10366450
2000 A human REV7 homolog that interacts with the polymerase zeta catalytic subunit hREV3 and the spindle assembly checkpoint protein hMAD2. The Journal of biological chemistry 171 10660610
2020 TRIP13 regulates DNA repair pathway choice through REV7 conformational change. Nature cell biology 126 31915374
2001 Inhibition of Cdh1-APC by the MAD2-related protein MAD2L2: a novel mechanism for regulating Cdh1. Genes & development 126 11459825
2001 MAD2B is an inhibitor of the anaphase-promoting complex. Genes & development 125 11459826
2018 SHLD2/FAM35A co-operates with REV7 to coordinate DNA double-strand break repair pathway choice. The EMBO journal 124 30154076
2007 A bacterial effector targets Mad2L2, an APC inhibitor, to modulate host cell cycling. Cell 122 17719540
2010 Crystal structure of human REV7 in complex with a human REV3 fragment and structural implication of the interaction between DNA polymerase zeta and REV1. The Journal of biological chemistry 107 20164194
2016 Biallelic inactivation of REV7 is associated with Fanconi anemia. The Journal of clinical investigation 106 27500492
1985 REV7, a new gene concerned with UV mutagenesis in yeast. Molecular & general genetics : MGG 105 3897794
2012 Structural basis of recruitment of DNA polymerase ζ by interaction between REV1 and REV7 proteins. The Journal of biological chemistry 89 22859296
2018 FAM35A associates with REV7 and modulates DNA damage responses of normal and BRCA1-defective cells. The EMBO journal 83 29789392
2006 Inactivation of human MAD2B in nasopharyngeal carcinoma cells leads to chemosensitization to DNA-damaging agents. Cancer research 76 16618761
2005 Complex formation of yeast Rev1 and Rev7 proteins: a novel role for the polymerase-associated domain. Molecular and cellular biology 75 16227619
2001 Impairment of MAD2B-PRCC interaction in mitotic checkpoint defective t(X;1)-positive renal cell carcinomas. Proceedings of the National Academy of Sciences of the United States of America 62 11717438
2003 Structure and enzymatic properties of a stable complex of the human REV1 and REV7 proteins. The Journal of biological chemistry 60 12529368
2015 REV7 is essential for DNA damage tolerance via two REV3L binding sites in mammalian DNA polymerase ζ. Nucleic acids research 57 25567983
2018 Rev7 dimerization is important for assembly and function of the Rev1/Polζ translesion synthesis complex. Proceedings of the National Academy of Sciences of the United States of America 51 30111544
2014 Suppression of REV7 enhances cisplatin sensitivity in ovarian clear cell carcinoma cells. Cancer science 50 24597627
2001 Trichosanthin interacts with acidic ribosomal proteins P0 and P1 and mitotic checkpoint protein MAD2B. European journal of biochemistry 49 11277934
2013 The REV7 subunit of DNA polymerase ζ is essential for primordial germ cell maintenance in the mouse. The Journal of biological chemistry 46 23463509
2012 The C-terminal domain of human Rev1 contains independent binding sites for DNA polymerase η and Rev7 subunit of polymerase ζ. FEBS letters 46 22828282
2007 Rev7/MAD2B links c-Jun N-terminal protein kinase pathway signaling to activation of the transcription factor Elk-1. Molecular and cellular biology 42 17296730
2018 H4K20me2 distinguishes pre-replicative from post-replicative chromatin to appropriately direct DNA repair pathway choice by 53BP1-RIF1-MAD2L2. Cell cycle (Georgetown, Tex.) 41 29160738
2009 MAD2B, a novel TCF4-binding protein, modulates TCF4-mediated epithelial-mesenchymal transdifferentiation. The Journal of biological chemistry 40 19443654
2021 REV7 directs DNA repair pathway choice. Trends in cell biology 39 34147298
2021 REV7: Jack of many trades. Trends in cell biology 38 33962851
2017 Dynamic feature of mitotic arrest deficient 2-like protein 2 (MAD2L2) and structural basis for its interaction with chromosome alignment-maintaining phosphoprotein (CAMP). The Journal of biological chemistry 37 28887307
2013 A critical function of Mad2l2 in primordial germ cell development of mice. PLoS genetics 37 24009519
2002 The property of DNA polymerase zeta: REV7 is a putative protein involved in translesion DNA synthesis and cell cycle control. Mutation research 36 12459441
2021 Mitotic syndicates Aurora Kinase B (AURKB) and mitotic arrest deficient 2 like 2 (MAD2L2) in cohorts of DNA damage response (DDR) and tumorigenesis. Mutation research. Reviews in mutation research 35 34083040
2016 Identification of the first small-molecule inhibitor of the REV7 DNA repair protein interaction. Bioorganic & medicinal chemistry 35 27448776
2015 Rev7/Mad2B plays a critical role in the assembly of a functional mitotic spindle. Cell cycle (Georgetown, Tex.) 35 26697843
2018 MAD2L2 inhibits colorectal cancer growth by promoting NCOA3 ubiquitination and degradation. Molecular oncology 34 29360267
2021 MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair. Nature communications 33 34521823
2019 REV7 confers radioresistance of esophagus squamous cell carcinoma by recruiting PRDX2. Cancer science 33 30657231
1994 Cloning and sequence of REV7, a gene whose function is required for DNA damage-induced mutagenesis in Saccharomyces cerevisiae. Yeast (Chichester, England) 32 7871890
2020 p31comet promotes homologous recombination by inactivating REV7 through the TRIP13 ATPase. Proceedings of the National Academy of Sciences of the United States of America 30 33051298
2010 The mitotic arrest deficient protein MAD2B interacts with the clathrin light chain A during mitosis. PloS one 28 21152103
2020 Inactivation of REV7 enhances chemosensitivity and overcomes acquired chemoresistance in testicular germ cell tumors. Cancer letters 27 32553781
2012 REV7 is required for anaphase-promoting complex-dependent ubiquitination and degradation of translesion DNA polymerase REV1. Cell cycle (Georgetown, Tex.) 27 23287467
2010 Overlapping in short motif sequences for binding to human REV7 and MAD2 proteins. Genes to cells : devoted to molecular & cellular mechanisms 27 20088965
2022 CHAMP1 binds to REV7/FANCV and promotes homologous recombination repair. Cell reports 26 36044844
2020 Rev7 loss alters cisplatin response and increases drug efficacy in chemotherapy-resistant lung cancer. Proceedings of the National Academy of Sciences of the United States of America 26 33144509
2013 A missense mutation in Rev7 disrupts formation of Polζ, impairing mouse development and repair of genotoxic agent-induced DNA lesions. The Journal of biological chemistry 26 24356953
2009 The mitotic arrest deficient protein MAD2B interacts with the small GTPase RAN throughout the cell cycle. PloS one 26 19753112
2009 Purification, crystallization and initial X-ray diffraction study of human REV7 in complex with a REV3 fragment. Acta crystallographica. Section F, Structural biology and crystallization communications 26 20054135
2003 Adenovirus ADP protein (E3-11.6K), which is required for efficient cell lysis and virus release, interacts with human MAD2B. Virology 26 12951035
2016 Knockdown of REV7 Inhibits Breast Cancer Cell Migration and Invasion. Oncology research 24 27712588
2016 Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 24 27889750
2015 MAD2B contributes to podocyte injury of diabetic nephropathy via inducing cyclin B1 and Skp2 accumulation. American journal of physiology. Renal physiology 23 25651564
2011 Mitotic arrest deficient protein MAD2B is overexpressed in human glioma, with depletion enhancing sensitivity to ionizing radiation. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 23 21514164
2019 REV7 has a dynamic adaptor region to accommodate small GTPase RAN/Shigella IpaB ligands, and its activity is regulated by the RanGTP/GDP switch. The Journal of biological chemistry 22 31484720
2022 MAD2B promotes podocyte injury through regulating Numb-dependent Notch 1 pathway in diabetic nephropathy. International journal of biological sciences 21 35342338
2018 Rev7 and 53BP1/Crb2 prevent RecQ helicase-dependent hyper-resection of DNA double-strand breaks. eLife 21 29697047
2015 REV7/MAD2L2: the multitasking maestro emerges as a barrier to recombination. The EMBO journal 21 25896508
2024 AURKB promotes bladder cancer progression by deregulating the p53 DNA damage response pathway via MAD2L2. Journal of translational medicine 20 38515112
2019 Structural basis for shieldin complex subunit 3-mediated recruitment of the checkpoint protein REV7 during DNA double-strand break repair. The Journal of biological chemistry 20 31796627
2022 MAD2L2 promotes replication fork protection and recovery in a shieldin-independent and REV3L-dependent manner. Nature communications 18 36075897
2007 Hepatocellular carcinoma-associated gene 2 interacts with MAD2L2. Molecular and cellular biochemistry 18 17541814
2014 Protection of neurons from high glucose-induced injury by deletion of MAD2B. Journal of cellular and molecular medicine 17 24444371
2020 Targeting REV7 effectively reverses 5-FU and oxaliplatin resistance in colorectal cancer. Cancer cell international 16 33292253
2016 MAD2B promotes tubular epithelial-to-mesenchymal transition and renal tubulointerstitial fibrosis via Skp2. Journal of molecular medicine (Berlin, Germany) 16 27488450
2012 A novel binding protein of single-minded 2: the mitotic arrest-deficient protein MAD2B. Neurogenetics 15 22660985
2003 Isolation and genetic characterization of the Neurospora crassa REV1 and REV7 homologs: evidence for involvement in damage-induced mutagenesis. DNA repair 15 12547396
2020 REV7 is required for processing AID initiated DNA lesions in activated B cells. Nature communications 14 32499490
2015 Destabilization of pluripotency in the absence of Mad2l2. Cell cycle (Georgetown, Tex.) 14 25928475
2017 MAD2B acts as a negative regulatory partner of TCF4 on proliferation in human dermal papilla cells. Scientific reports 13 28916740
2023 REV7 in Cancer Biology and Management. Cancers 12 36980607
2021 Upregulation of REV7 correlates with progression of malignant melanoma. Pathology international 12 34637584
2017 MAD2L2 Promotes Open Chromatin in Embryonic Stem Cells and Derepresses the Dppa3 Locus. Stem cell reports 11 28330620
2016 MAD2B-mediated SnoN downregulation is implicated in fibroblast activation and tubulointerstitial fibrosis. American journal of physiology. Renal physiology 11 27122545
2024 MAD2L2, a key regulator in ovarian cancer and promoting tumor progression. Scientific reports 10 38167649
2021 MAD2B-mediated cell cycle reentry of podocytes is involved in the pathogenesis of FSGS. International journal of biological sciences 10 34803506
2020 Increased expression of REV7 in small cell lung carcinomas and its association with tumor cell survival and proliferation. Pathology international 10 33112501
2015 Lack of Rev7 function results in development of tubulostromal adenomas in mouse ovary. Molecular and cellular endocrinology 10 26004212
2022 Disrupting the MAD2L2-Rev1 Complex Enhances Cell Death upon DNA Damage. Molecules (Basel, Switzerland) 9 35163901
2023 MAD2B Blunts Chronic Unpredictable Stress and Corticosterone Stimulation-Induced Depression-Like Behaviors in Mice. The international journal of neuropsychopharmacology 8 36573299
2020 MDA-MB-157 Cell Line Presents High Levels of MAD2L2 and Dysregulated Mitosis. Anticancer research 8 32988869
2017 Rev7, the regulatory subunit of Polζ, undergoes UV-induced and Cul4-dependent degradation. The FEBS journal 8 28440919
2010 Rev1, Rev3, or Rev7 siRNA Abolishes Ultraviolet Light-Induced Translesion Replication in HeLa Cells: A Comprehensive Study Using Alkaline Sucrose Density Gradient Sedimentation. Journal of nucleic acids 8 21151666
2023 Inactivation of Mad2B Enhances Apoptosis in Human Cervical Cancer Cell Line upon Cisplatin-Induced DNA Damage. Biomolecules & therapeutics 7 36642928
2023 The promoting effect and mechanism of MAD2L2 on stemness maintenance and malignant progression in glioma. Journal of translational medicine 7 38017538
2023 REV7 is involved in outcomes of platinum-based chemotherapy in pancreatic cancer by controlling the DNA damage response. Cancer science 7 38130032
2020 CDH1 binds MAD2L2 in a Rev1-like pattern. Biochemical and biophysical research communications 7 32811646
2020 MAD2B contributes to parietal epithelial cell activation and crescentic glomerulonephritis via Skp2. American journal of physiology. Renal physiology 7 32830536
2012 Crystallization and X-ray diffraction analysis of the ternary complex of the C-terminal domain of human REV1 in complex with REV7 bound to a REV3 fragment involved in translesion DNA synthesis. Acta crystallographica. Section F, Structural biology and crystallization communications 7 22869133
2022 Evolution of Rev7 interactions in eukaryotic TLS DNA polymerase Polζ. The Journal of biological chemistry 6 36592930
2024 Saccharomyces cerevisiae Rev7 promotes non-homologous end-joining by blocking Mre11 nuclease and Rad50's ATPase activities and homologous recombination. eLife 5 39630591
2004 Isolation and characterization of the Xenopus laevis orthologs of the human papillary renal cell carcinoma-associated genes PRCC and MAD2L2 (MAD2B). Cytogenetic and genome research 5 15218244
2025 Targeting the AURKB-MAD2L2 Axis Disrupts the DNA Damage Response and Glycolysis to Inhibit Colorectal Cancer Progression. Frontiers in bioscience (Landmark edition) 4 40018943
2024 REV7-p53 interaction inhibits ATM-mediated DNA damage signaling. Cell cycle (Georgetown, Tex.) 4 38557443
2023 Bridging Gaps in HDR Improvement: The Role of MAD2L2, SCAI, and SCR7. International journal of molecular sciences 4 37047677
2022 Conditional deletion of MAD2B in forebrain neurons enhances hippocampus-dependent learning and memory in mice. Frontiers in cellular neuroscience 4 36212696
2021 Mitotic Arrest-Deficient 2 Like 2 (MAD2L2) Interacts with Escherichia coli Effector Protein EspF. Life (Basel, Switzerland) 4 34575120
2021 Inhibition of MAD2B alleviates venous neointimal formation by suppressing VSMCs proliferation and migration. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 4 34605572
2015 Attenuation of glomerular endothelial cells from high glucose-induced injury by blockade of MAD2B. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 4 25547045