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Showing MAD2L2 — REV7 is a alias.

MAD2L2

Mitotic spindle assembly checkpoint protein MAD2B · UniProt Q9UI95

Length
211 aa
Mass
24.3 kDa
Annotated
2026-06-10
100 papers in source corpus 47 papers cited in narrative 47 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAD2L2 (REV7/MAD2B/FANCV) is a HORMA-domain adaptor that uses a multivalent 'safety-belt' surface to bind structurally diverse partners and thereby coordinates DNA damage tolerance, double-strand break (DSB) repair pathway choice, and mitotic cell-cycle control (PMID:20164194, PMID:28887307, PMID:31484720). In translesion synthesis, REV7 is the non-catalytic subunit of DNA polymerase zeta, binding the catalytic subunit REV3L through two short sequence motifs and recruiting REV1 via a distinct interface, with REV7 dimerization tethered by the two REV3 motifs being required for assembly of a functional REV1/pol zeta complex (PMID:20164194, PMID:22859296, PMID:25567983, PMID:30111544); this activity underlies damage-induced mutagenesis and resistance to UV and crosslinking agents (PMID:3897794, PMID:25567983), and a point mutation (C70R) that severs the REV7–REV3 interaction abolishes damage tolerance and causes germ-cell loss and infertility (PMID:24356953). REV7 is the central subunit of the shieldin complex (with SHLD1, SHLD2/FAM35A, SHLD3), which is recruited to DSBs and telomeres through the H4K20me2–53BP1–RIF1 axis and inhibits 5' end resection to enforce NHEJ over homologous recombination; its loss restores resection in BRCA1-deficient cells and causes PARP-inhibitor resistance (PMID:25799992, PMID:25799990, PMID:30046110, PMID:30154076, PMID:29160738). Shieldin assembly depends on SHLD2-driven REV7 dimerization and on REV7's C-terminal wrapping around SHLD3, and is reversed by TRIP13-catalyzed closed-to-open conformational switching together with p31comet, which also disassembles the REV7–REV3 complex; competing seatbelt ligands such as CHAMP1 likewise tune this balance (PMID:31796627, PMID:31915374, PMID:33051298, PMID:34521823, PMID:36044844). Independently of shieldin, REV7 protects and restarts stalled replication forks in a REV3L/REV1-dependent manner by limiting MRE11 resection (PMID:36075897). In mitotic control, MAD2L2 inhibits both CDH1-APC and CDC20-APC by binding the activators rather than the core APC (PMID:11459826, PMID:11459825), and biallelic inactivating REV7 mutations cause Fanconi anemia (REV7 = FANCV) (PMID:27500492).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1985 High

    Established that REV7 function is needed for damage-induced mutagenesis, placing it in a defined DNA-damage tolerance genetic pathway before any molecular activity was known.

    Evidence Yeast mutant screen with UV survival/reversion and RAD6 epistasis analysis

    PMID:3897794 PMID:7871890

    Open questions at the time
    • No biochemical activity assigned
    • Mammalian ortholog and protein partners unknown
  2. 1999 Medium

    Identified the human gene MAD2L2 as a MAD2 homolog, raising the question of whether it functioned in the spindle checkpoint or elsewhere.

    Evidence Gene isolation, homology analysis, and chromosomal mapping with tumor mutation screening

    PMID:10366450

    Open questions at the time
    • No functional mechanism established beyond homology
    • Relationship to MAD2L1 function unresolved
  3. 2001 High

    Showed that, unlike its MAD2 paralog, MAD2L2 inhibits APC by targeting the activators CDH1 and CDC20 rather than the core, defining a distinct cell-cycle regulatory role.

    Evidence In vitro APC ubiquitin-ligase and binding assays, Xenopus egg-extract reconstitution

    PMID:11459825 PMID:11459826

    Open questions at the time
    • Physiological context of APC inhibition vs. spindle checkpoint unclear
    • Structural basis of activator binding not defined
  4. 2000 Medium

    Connected human REV7 to translesion synthesis by demonstrating it binds the pol zeta catalytic subunit REV3, linking it to the yeast mutagenesis phenotype.

    Evidence Yeast two-hybrid screen with interaction domain mapping

    PMID:10660610

    Open questions at the time
    • No reconstitution of pol zeta activity
    • REV1 interaction not yet defined
  5. 2007 High

    Revealed MAD2L2 as a target of pathogen subversion and a signaling hub, with the Shigella effector IpaB neutralizing its APC-inhibitory function and REV7 promoting Elk-1/JNK signaling after damage.

    Evidence Cyclin B1 ubiquitination assays, infection models, in vivo intestinal model, kinase and reporter assays

    PMID:17296730 PMID:17719540

    Open questions at the time
    • Structural basis of IpaB binding not yet resolved
    • Breadth of REV7 signaling functions unclear
  6. 2012 High

    Defined the structural logic of pol zeta recruitment, showing REV7 acts as an adaptor whose REV3-bound surface and a distinct REV1-CTD interface enable polymerase switching during TLS.

    Evidence Crystal structures of REV7–REV3 and REV1-CTD–REV7–REV3 ternary complex; NMR interface mapping

    PMID:20088965 PMID:20164194 PMID:22828282 PMID:22859296

    Open questions at the time
    • Catalytic mechanism of the assembled pol zeta not addressed
    • Conformational regulation of REV7 not yet known
  7. 2013 High

    Demonstrated in vivo that the REV7–REV3 TLS interaction is essential for germ-cell maintenance and genome stability, separating the TLS function from spindle-checkpoint roles.

    Evidence Mouse positional cloning of the C70R mutation, transgenic rescue, knockouts, cell-cycle and γH2AX analyses

    PMID:23463509 PMID:24009519 PMID:24356953

    Open questions at the time
    • Mechanism of chromatin-state transitions partially defined
    • Tissue specificity of phenotypes not fully explained
  8. 2015 High

    Established REV7 as a TLS-independent regulator of DSB repair pathway choice that blocks end resection downstream of 53BP1–RIF1, explaining its impact on BRCA1-deficient cancers and PARPi response.

    Evidence Genetic KO/knockdown in mouse and human cells, resection/HR assays, telomere fusion assays, chromatin recruitment epistasis

    PMID:25567983 PMID:25799990 PMID:25799992

    Open questions at the time
    • Identity of effector subunits enforcing resection block not yet known
    • How a single protein toggles between TLS and end-protection unresolved
  9. 2016 High

    Identified REV7 as the Fanconi anemia gene FANCV, linking its loss to a defined human chromosome-instability disease.

    Evidence Patient-cell analysis, WT rescue, CRISPR/Cas9 KO, chromosome-break and γH2AX assays

    PMID:27500492

    Open questions at the time
    • Which REV7 function (TLS vs. shieldin) underlies FA not fully dissected
  10. 2018 High

    Resolved the resection-blocking effector by identifying the shieldin complex (REV7–SHLD1/2/3) and showing REV7 dimerization governs assembly of both shieldin and pol zeta.

    Evidence Mouse genetics, MS interactomics, co-IP, CSR/resection assays, structural and biochemical dimerization analysis

    PMID:29160738 PMID:29697047 PMID:29789392 PMID:30046110 PMID:30111544 PMID:30154076

    Open questions at the time
    • How shieldin physically blocks nucleases at the DNA end not defined
    • Quantitative interplay of dimerization across complexes unclear
  11. 2020 High

    Defined the conformational switch governing REV7 activity, showing TRIP13 and p31comet convert REV7 from closed to open to dissociate both shieldin and pol zeta, controlling repair-pathway and PARPi-resistance outcomes.

    Evidence Biochemical conformational assays, co-IP, genetic KO, PARPi sensitivity, conditional B-cell KO with epistasis

    PMID:31915374 PMID:32499490 PMID:33051298

    Open questions at the time
    • Upstream signals controlling TRIP13/p31comet activity unknown
    • How closed/open ratio is spatially regulated at lesions unclear
  12. 2019 High

    Provided structural proof that REV7's safety-belt accommodates diverse ligands (RAN, IpaB, SHLD3, CAMP), with nucleotide-state-dependent RAN binding linking REV7 to cell-cycle regulation.

    Evidence Multiple X-ray crystal structures with binding-kinetics and nucleotide-preference assays

    PMID:28887307 PMID:31484720 PMID:31796627

    Open questions at the time
    • Physiological consequences of RAN/CAMP binding not fully established
    • Competition hierarchy among seatbelt ligands in cells unclear
  13. 2022 High

    Distinguished a shieldin-independent fork-protection role and identified competing seatbelt ligands (CHAMP1) that rebalance repair choice, broadening REV7's genome-maintenance reach.

    Evidence DNA fiber and SMARD assays with REV3L/REV1/MRE11 epistasis; co-IP, resection/HR and PARPi assays for CHAMP1; APC activator binding mapping

    PMID:32811646 PMID:36044844 PMID:36075897

    Open questions at the time
    • Mechanism of fork protection at the molecular level not resolved
    • In vivo relevance of CHAMP1 competition not established
  14. 2024 Medium

    Extended REV7's signaling roles by linking it to p53 regulation and AURKB-dependent DDR, hinting at integration of repair with damage-response signaling.

    Evidence Co-IP, phosphorylation assays, knockdown/overexpression rescue, xenografts

    PMID:38515112 PMID:38557443

    Open questions at the time
    • Single-lab co-IP without reciprocal structural validation
    • Direct vs. indirect effects on p53 phosphorylation not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How REV7's single seatbelt surface is allocated among its many competing partners in space and time—and which signals choose between its TLS, shieldin, fork-protection, and APC-inhibitory functions—remains unresolved.
  • No unified model of partner-selection regulation
  • Upstream determinants of conformational state in vivo unknown
  • Quantitative competition among seatbelt ligands uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 4 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-73894 DNA Repair 5 R-HSA-1640170 Cell Cycle 3 R-HSA-69306 DNA Replication 3 R-HSA-1643685 Disease 1
Partners
53BP1CHAMP1RANREV1REV3LSHLD2SHLD3TRIP13
Complex memberships
DNA polymerase zeta (REV3L-REV7)REV1/pol zeta TLS complexshieldin (REV7-SHLD1-SHLD2-SHLD3)

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1985 REV7 (yeast ortholog) is required for UV-induced mutagenesis in Saccharomyces cerevisiae and belongs to the RAD6 epistasis group for UV survival, establishing its role in damage-induced mutagenesis. Genetic mutant screen, UV survival and reversion assays, epistasis analysis Molecular & general genetics High 3897794
1994 Yeast REV7 gene was cloned and sequenced; its function is required for DNA damage-induced mutagenesis but is not essential for viability. Complementation cloning, sequence analysis Yeast Medium 7871890
1999 Human MAD2B (MAD2L2) gene was isolated and characterized as homologous to the spindle checkpoint gene MAD2 (MAD2L1); chromosomal localization was determined (chromosome 1p36). Gene isolation, sequence homology analysis, chromosomal localization, tumor mutation screening Genomics Medium 10366450
2000 Human REV7 (hREV7) interacts with hREV3 (catalytic subunit of DNA polymerase zeta) and with hMAD2 (but not hMAD1), establishing hREV7 as a component of the human pol zeta complex; interaction domains between hREV3 and hREV7 were determined. Yeast two-hybrid screen, interaction domain mapping The Journal of biological chemistry Medium 10660610
2001 MAD2B (MAD2L2) inhibits both CDH1-APC and CDC20-APC (anaphase-promoting complex) by targeting CDH1 and CDC20 directly, not APC itself; unlike MAD2, MAD2B does not interact with MAD1, indicating it relays a distinct cellular signal. In vitro APC activity assays, binding assays Genes & development High 11459826
2001 MAD2L2 specifically binds and inhibits CDH1-APC (but not CDC20-APC in contrast to MAD2); proposed mechanism is inhibition of substrate release from APC, paralleling MAD2's effect on CDC20. In vitro APC activity assays, binding assays, Xenopus egg extract reconstitution Genes & development High 11459825
2001 MAD2B interacts with PRCC (papillary renal cell carcinoma protein); the PRCCTFE3 fusion protein retains the MAD2B interaction domain but this interaction is impaired, leading to mitotic checkpoint defects in t(X;1)-positive RCCs. Co-immunoprecipitation, transfection assays, mitotic checkpoint assays Proceedings of the National Academy of Sciences Medium 11717438
2003 Human REV1 and REV7 proteins form a stable heterodimer in solution; however, human REV7 does not influence the stability, substrate specificity, or kinetic parameters of REV1's transferase activity (negative finding for functional stimulation in humans, contrasting with yeast Rev7 stimulating Rev3). Protein purification, biochemical transferase assays, kinetic analysis The Journal of biological chemistry Medium 12529368
2005 In yeast, Rev1 forms a stable complex with Rev7 that copurifies; the polymerase-associated domain (PAD) of Rev1 mediates its binding to Rev7, revealing a novel protein-protein interaction role for the PAD. Protein copurification, binding assays, domain mapping Molecular and cellular biology Medium 16227619
2007 Human Rev7/MAD2B interacts with the transcription factor Elk-1 and promotes Elk-1 phosphorylation by JNK MAP kinases, thereby upregulating Elk-1 target gene expression (e.g., egr-1) following DNA damage. Co-immunoprecipitation, kinase assays, reporter gene assays, loss-of-function Molecular and cellular biology Medium 17296730
2007 The Shigella effector IpaB binds directly to Mad2L2 and causes unscheduled APC activation (by neutralizing Mad2L2's APC-inhibitory function), leading to G2/M cell cycle arrest dependent on IpaB/Mad2L2 interaction, which promotes bacterial colonization. Cyclin B1 ubiquitination assay, synchronized cell infection, siRNA knockdown, in vivo rabbit intestinal model Cell High 17719540
2009 MAD2B interacts with the small GTPase RAN throughout the cell cycle; during mitosis, they co-localize at the spindle; the interaction domain of RAN maps to a C-terminal 60 amino acid moiety, and MAD2B must be full-length. Yeast two-hybrid, endogenous co-immunoprecipitation, confocal co-localization, cell cycle fractionation PloS one Medium 19753112
2009 MAD2B interacts with TCF4; this interaction abolishes TCF4's DNA-binding ability and blocks TCF4-mediated transactivation; MAD2B knockdown leads to epithelial-mesenchymal transdifferentiation by de-repressing TCF4-mediated Slug expression. Yeast two-hybrid, co-immunoprecipitation, EMSA, TOPFLASH reporter assay, chromatin immunoprecipitation, siRNA knockdown The Journal of biological chemistry Medium 19443654
2010 Crystal structure of human REV7 in complex with a REV3 fragment (residues 1847-1898) was solved; the structure reveals the mechanism of REV7-REV3 interaction and shows that the REV7-REV3 interface creates a structural platform for REV1 binding, defining REV7 as an adaptor protein recruiting pol zeta to lesion sites. X-ray crystallography, structural analysis, functional complementation The Journal of biological chemistry High 20164194
2010 Defined short sequence motifs in REV3 are necessary and sufficient for REV7 binding; MAD2 (MAD2L1) also binds the REV7-binding sequence in REV3, but REV7 does not bind the MAD2-binding sequences in MAD1 or CDC20, establishing distinct but overlapping short motif recognition between REV7 and MAD2. Binding assays, peptide competition, domain mapping Genes to cells Medium 20088965
2010 MAD2B interacts with clathrin light chain A (CLTA) during G2/M phase and co-localizes with CLTA at the mitotic spindle; MAD2B depletion causes CLTA redistribution away from the spindle and increased chromosome misalignment. Yeast two-hybrid, GST pull-down, endogenous co-immunoprecipitation, confocal microscopy, siRNA knockdown PloS one Medium 21152103
2012 Crystal structure of the ternary complex of human REV1 C-terminal domain, REV7, and a REV3 fragment was solved; the REV1 CTD uses a four-helix bundle to interact with REV7 via a conserved mammalian linker region, using a distinct interface from other TLS polymerase binding sites, providing the structural basis for pol zeta recruitment and polymerase switching. X-ray crystallography, structural analysis The Journal of biological chemistry High 22859296
2012 NMR spectroscopy demonstrates that the Rev1 C-terminal domain uses independent interaction interfaces to simultaneously bind pol eta and REV7 (subunit of pol zeta), enabling Rev1 to serve as a scaffold accommodating multiple polymerases for TLS. NMR spectroscopy, binding interface mapping FEBS letters High 22828282
2012 REV7 is required for APC/C-mediated polyubiquitination and proteasomal degradation of REV1; REV7 depletion stabilizes REV1 by preventing its polyubiquitination, while REV7 overexpression augments REV1 degradation; the N-terminal region of REV1 contains both the APC degron and an additional REV7-binding domain. Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, overexpression Cell cycle Medium 23287467
2013 A missense mutation (C70R) in Rev7 disrupts its interaction with REV3 (catalytic subunit of pol zeta), causing infertility, primordial germ cell loss, increased apoptosis, S-phase arrest with DNA damage accumulation after mitomycin C; Rev7 C70R does not affect the mitotic spindle assembly checkpoint. Positional cloning, transgenic rescue, protein interaction assay, cell cycle analysis, gamma-H2AX foci The Journal of biological chemistry High 24356953
2013 Mad2l2 is essential for primordial germ cell (PGC) maintenance in mice; Mad2l2-/- PGCs fail to arrest in G2 phase and fail to transition from H3K9me2 to H3K27me3 chromatin configuration; Mad2l2 interacts with histone methyltransferases G9a and GLP (downregulating H3K9me2) and inhibits Cdk1 (causing G2 arrest), which allows Ezh2 to upregulate H3K27me3. Knockout mouse phenotyping, immunofluorescence, co-immunoprecipitation, transfection of fibroblasts with interaction assays PLoS genetics High 24009519
2013 REV7 is essential for primordial germ cell (PGC) maintenance and fertility in mice; Rev7-/- mice show progressive PGC loss during migration with increased apoptosis; DNA damage accumulation and increased histone methylation were detected in Rev7-/- embryos; REV7 is required for prevention of apoptotic cell death in PGCs. Knockout mouse generation, embryo analysis, apoptosis assays, immunostaining The Journal of biological chemistry High 23463509
2015 REV7 (MAD2L2) loss in mouse and human cells re-establishes CTIP-dependent end resection of DSBs in BRCA1-deficient cells, restoring homologous recombination and causing PARP inhibitor resistance; REV7 is recruited to DSBs via the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway; REV7 promotes NHEJ by blocking HR and end resection downstream of 53BP1; ATM inhibition reverses PARPi resistance caused by REV7 loss. Genetic KO/knockdown in mouse and human cells, resection assays, HR assays, PARPi sensitivity assays, chromatin recruitment epistasis Nature High 25799992
2015 MAD2L2 accumulates at uncapped telomeres and promotes NHEJ-mediated chromosome end fusion; MAD2L2 inhibits 5' end resection at DSBs and telomeres; its activity depends on ATM, RNF8, RNF168, 53BP1, and RIF1 but not PTIP, REV1, or REV3; MAD2L2 controls DSB repair independently of its TLS role. Functional genetic screening, knockdown, telomere overhang assays, immunofluorescence, class switch recombination assays, epistasis Nature High 25799990
2015 REV7 is essential for DNA damage tolerance via its interaction with two distinct REV7-binding sites in mammalian REV3L (residues 1877-1887 and 1993-2003); mutation of both binding sites eliminates REV3L-REV7 interaction and fails to prevent spontaneous chromosome breaks or confer UV and cisplatin resistance. In vivo co-immunoprecipitation, mutagenesis, functional complementation in REV7-/- cells Nucleic acids research High 25567983
2015 Rev7/Mad2B is required for functional mitotic spindle assembly; Rev7-depleted cells accumulate monoastral and abnormal spindles with misaligned chromosomes; Rev7 physically interacts with RAN and this interaction may mediate spindle organization; Rev7 depletion does not compromise spindle assembly checkpoint activity. siRNA knockdown, live cell imaging, spindle assembly analysis, co-immunoprecipitation Cell cycle Medium 26697843
2016 Biallelic inactivating mutations in REV7 (FANCV) cause Fanconi anemia; patient-derived cells show increased chromosome breaks and G2/M accumulation upon crosslinking agents, γH2AX and 53BP1 foci; WT REV7 expression rescues normal phenotypes; CRISPR/Cas9 inactivation of REV7 in non-FA cells produces FA phenotype; REV7 is thereby identified as FANCV. Patient cell analysis, WT rescue, CRISPR/Cas9 KO, chromosome break assays, G2/M accumulation, γH2AX foci The Journal of clinical investigation High 27500492
2017 Crystal structures of MAD2L2 in complex with CAMP (chromosome alignment-maintaining phosphoprotein) fragments reveal that CAMP's 'WK' motif mediates binding to MAD2L2; the MAD2L2-CAMP interaction creates a distinct interface compared to REV3 binding; one crystal form shows a dimeric MAD2L2-CAMP structure with C-terminal domain swapping, providing evidence for the dynamic nature of MAD2L2 structure. X-ray crystallography in two crystal forms, structure-based interaction analysis The Journal of biological chemistry High 28887307
2017 REV7 undergoes ubiquitin/proteasome-mediated degradation upon UV irradiation; the N-terminal destruction box of REV7 acts as the degron; Cul4A/B are the putative E3 ubiquitin ligases; HR23B physically interacts with and colocalizes with REV7 in nuclear foci post-UV and protects REV7 from accelerated degradation; degradation is NER-pathway dependent (observed with UV and 4-NQO but not cisplatin). Protein degradation assays, mutagenesis of destruction box, co-immunoprecipitation, colocalization, shRNA knockdown The FEBS journal Medium 28440919
2018 MAD2L2 (REV7) inhibits NCOA3 through a mechanism requiring p38 activation, which phosphorylates NCOA3 leading to its ubiquitination and proteasomal degradation; MAD2L2 was identified as an NCOA3 interaction partner by IP-MS. IP-mass spectrometry, co-immunoprecipitation, overexpression/knockdown, ubiquitination assays, p38 inhibitor Molecular oncology Medium 29360267
2018 53BP1 cooperates with REV7 to promote NHEJ during class-switch recombination (CSR) but REV7 is not required for 53BP1-dependent V(D)J recombination; shieldin (comprising REV7, SHLD1/c20orf196, SHLD2/FAM35A, SHLD3/FLJ26957) was identified as a four-subunit complex essential for REV7-dependent DNA end protection and NHEJ in CSR but dispensable for REV7-dependent ICL repair. Genetic mouse models, mass spectrometry, co-immunoprecipitation, CSR assays, epistasis Nature High 30046110
2018 SHLD2 (FAM35A) is a REV7 interactor identified by MS-based proteomics; FAM35A accumulates at DSBs in a 53BP1-, RIF1-, and REV7-dependent manner; FAM35A, REV7, and SHLD1 form a complex promoting NHEJ and limiting HR by antagonizing DNA end resection. Mass spectrometry proteomics, co-immunoprecipitation, knockdown, CSR assays, resection assays The EMBO journal High 30154076
2018 FAM35A (SHLD2) associates with REV7/RIF1/53BP1; FAM35A knockdown causes sensitivity to DNA-damaging agents; in BRCA1-mutant cells, FAM35A depletion increases resistance to camptothecin by allowing more efficient DNA end processing. Proteomics, co-immunoprecipitation, siRNA knockdown, clonogenic survival assays The EMBO journal Medium 29789392
2018 H4K20 dimethylation (H4K20me2) recruits the 53BP1-RIF1-MAD2L2 complex to DSBs; replication-associated 2-fold dilution of H4K20me2 promotes release of this complex and favors BRCA1 access; MAD2L2, like 53BP1 and RIF1, suppresses DSB accumulation of BRCA1. Chromatin fractionation, co-immunoprecipitation, immunofluorescence, cell cycle analysis Cell cycle Medium 29160738
2018 Rev7 dimerization is required for assembly and function of the Rev1/pol zeta TLS complex; Rev7 forms homodimers when tethered by the two RBMs of Rev3 and heterodimerizes with Mad2 and p31comet via the canonical HORMA dimerization interface; the Rev7 dimer binds only one copy of Rev1; mutation of the Rev7 dimer interface increases cellular sensitivity to DNA damage. In vitro binding assays, structural analysis, functional complementation in Rev7-/- cells Proceedings of the National Academy of Sciences High 30111544
2018 Rev7 and 53BP1/Crb2 specifically repress long-range DSB resection through the RecQ helicase-dependent pathway (not Exo1), preventing hyper-resection in S. pombe; this mechanism is linked to PARPi resistance in BRCA1-deficient cells. Single-cell microscopy resection assay in S. pombe, genetic epistasis eLife Medium 29697047
2019 Crystal structures of REV7 in complex with RAN and IpaB fragments were solved; both RAN and IpaB bind the 'safety belt' region of REV7 causing rearrangement of the C-terminal beta-sheet; REV7 preferentially binds GTP-bound RAN, suggesting the RAN GTP/GDP switch regulates REV7 activity in cell cycle control. X-ray crystallography (2.00-2.35 Å resolution), biochemical binding assays The Journal of biological chemistry High 31484720
2019 Crystal structures of REV7 in complex with SHLD3's REV7-binding domain (RBD) were solved at 2.2-2.3 Å; SHLD3 uses an N-terminal loop and C-terminal alpha-helix for REV7 binding; the REV7 'safety belt' region retards RBD dissociation (low-nanomolar affinity); both structural elements are indispensable for high-affinity binding. X-ray crystallography, binding kinetics analysis, in vitro and in vivo binding assays The Journal of biological chemistry High 31796627
2020 TRIP13 ATPase catalyzes the conversion of REV7 from an active 'closed' conformation to an inactive 'open' conformation, dissociating REV7-Shieldin to promote HDR; TRIP13 similarly disassembles the REV7-REV3 TLS complex, inhibiting error-prone TLS; TRIP13 overexpression confers PARPi resistance in BRCA1-deficient cancers. Biochemical conformational assays, co-immunoprecipitation, genetic KO, PARPi resistance assays Nature cell biology High 31915374
2020 p31comet binds the REV7-Shieldin complex, promotes REV7 inactivation (via TRIP13), causes dissociation from SHLD3, and promotes DNA end resection and PARPi resistance; p31comet also releases REV7 from REV3 in pol zeta, counteracting TLS. Co-immunoprecipitation, chromatin fractionation, PARPi sensitivity assays, overexpression/knockdown Proceedings of the National Academy of Sciences Medium 33051298
2020 REV7 is required for B cell survival upon AID-deamination independently of its roles in DSBR, G2/M transition, or REV1-mediated TLS; REV7-dependent TLS across UNG-processed apurinic/apyrimidinic (AP) sites is required for cell survival upon AID/APOBEC deamination. Conditional KO mouse models (B cell specific), genetic epistasis (AID/REV7 double KO rescue), cell death assays Nature communications High 32499490
2021 MAD2L2 dimerization (mediated by SHLD2) accelerates MAD2L2-SHLD3 interaction and is required for shieldin complex assembly and NHEJ function; MAD2L2 wraps its C-terminus around SHLD3 creating a stable complex; appropriate TRIP13 levels are important for proper shieldin (dis)assembly. Co-immunoprecipitation, mutagenesis, NHEJ assays, CSR assays, interaction kinetics Nature communications High 34521823
2022 CHAMP1 binds directly to REV7 via the REV7 seatbelt/C-terminal domain (competing with SHLD3), reduces shieldin complex levels, increases DSB end resection, and activates HR repair; CHAMP1 also interacts with POGZ in a heterochromatin complex promoting HR; CHAMP1 overexpression confers PARPi resistance. Co-immunoprecipitation, knockdown, resection assays, HR assays, PARPi sensitivity Cell reports Medium 36044844
2022 MAD2L2 promotes replication fork protection and restart independently of shieldin; MAD2L2 loss leads to uncontrolled MRE11-dependent resection of stalled forks and ssDNA accumulation; fork protection by MAD2L2 requires REV3L and REV1 (TLS partners) but not shieldin subunits. Single-molecule DNA fiber assays, genetic epistasis, MRE11 inhibition, SMARD analysis Nature communications High 36075897
2022 CDH1 interacts with MAD2L2 using the same C-terminal residues that REV1 uses (Rev1-like binding pattern); MAD2L2's C-terminus interface is essential for both CDH1-MAD2L2 binding and MAD2L2 homodimerization. Mutagenesis of MAD2L2, co-immunoprecipitation in human cell line Biochemical and biophysical research communications Medium 32811646
2024 REV7 binds directly to p53 and blocks ATM-dependent p53 Ser15 phosphorylation; REV7 is also involved in p53 destabilization, revealing a novel function of REV7 in DSB-induced p53 signaling. Co-immunoprecipitation, phosphorylation assays, knockdown/overexpression Cell cycle Medium 38557443
2024 AURKB interacts with and modulates expression of MAD2L2 in bladder cancer cells; AURKB knockdown effects (suppression of proliferation/migration, cell cycle arrest, senescence) are rescued by MAD2L2 overexpression, placing MAD2L2 downstream of AURKB in a DDR pathway affecting p53. Co-immunoprecipitation, knockdown/overexpression rescue experiments, xenograft Journal of translational medicine Medium 38515112

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 502 25799992
2018 53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ. Nature 254 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 129 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 126 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
2016 Biallelic inactivation of REV7 is associated with Fanconi anemia. The Journal of clinical investigation 108 27500492
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
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 63 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 58 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
2018 H4K20me2 distinguishes pre-replicative from post-replicative chromatin to appropriately direct DNA repair pathway choice by 53BP1-RIF1-MAD2L2. Cell cycle (Georgetown, Tex.) 44 29160738
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
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
2013 A critical function of Mad2l2 in primordial germ cell development of mice. PLoS genetics 38 24009519
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
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 36 34083040
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
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
2021 MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair. Nature communications 34 34521823
2019 REV7 confers radioresistance of esophagus squamous cell carcinoma by recruiting PRDX2. Cancer science 34 30657231
2018 MAD2L2 inhibits colorectal cancer growth by promoting NCOA3 ubiquitination and degradation. Molecular oncology 34 29360267
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
2012 REV7 is required for anaphase-promoting complex-dependent ubiquitination and degradation of translesion DNA polymerase REV1. Cell cycle (Georgetown, Tex.) 28 23287467
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
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
2015 MAD2B contributes to podocyte injury of diabetic nephropathy via inducing cyclin B1 and Skp2 accumulation. American journal of physiology. Renal physiology 25 25651564
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
2022 MAD2B promotes podocyte injury through regulating Numb-dependent Notch 1 pathway in diabetic nephropathy. International journal of biological sciences 23 35342338
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
2024 AURKB promotes bladder cancer progression by deregulating the p53 DNA damage response pathway via MAD2L2. Journal of translational medicine 22 38515112
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
2018 Rev7 and 53BP1/Crb2 prevent RecQ helicase-dependent hyper-resection of DNA double-strand breaks. eLife 22 29697047
2015 REV7/MAD2L2: the multitasking maestro emerges as a barrier to recombination. The EMBO journal 21 25896508
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 19 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
2023 MAD2B Blunts Chronic Unpredictable Stress and Corticosterone Stimulation-Induced Depression-Like Behaviors in Mice. The international journal of neuropsychopharmacology 9 36573299
2022 Disrupting the MAD2L2-Rev1 Complex Enhances Cell Death upon DNA Damage. Molecules (Basel, Switzerland) 9 35163901
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
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 8 22869133
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
2022 Evolution of Rev7 interactions in eukaryotic TLS DNA polymerase Polζ. The Journal of biological chemistry 6 36592930
2024 REV7-p53 interaction inhibits ATM-mediated DNA damage signaling. Cell cycle (Georgetown, Tex.) 5 38557443
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 Microglia-derived ADAM9 promote GHRH neurons pyroptosis by Mad2L2-JNK-caspase-1 pathway in subarachnoid hemorrhage. Journal of neuroinflammation 4 39563331
2023 The MAD2B-APC/C-MDM2 axis mediates acute kidney injury by modulating p53. The FEBS journal 4 37002708
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 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

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