{"gene":"MAD2L2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1985,"finding":"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.","method":"Genetic mutant screen, UV survival and reversion assays, epistasis analysis","journal":"Molecular & general genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — foundational genetic epistasis in yeast, replicated across multiple alleles","pmids":["3897794"],"is_preprint":false},{"year":1994,"finding":"Yeast REV7 gene was cloned and sequenced; its function is required for DNA damage-induced mutagenesis but is not essential for viability.","method":"Complementation cloning, sequence analysis","journal":"Yeast","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic complementation, single lab, cloning and functional verification","pmids":["7871890"],"is_preprint":false},{"year":1999,"finding":"Human MAD2B (MAD2L2) gene was isolated and characterized as homologous to the spindle checkpoint gene MAD2 (MAD2L1); chromosomal localization was determined (chromosome 1p36).","method":"Gene isolation, sequence homology analysis, chromosomal localization, tumor mutation screening","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gene characterization, single lab, no functional mechanism established beyond homology identification","pmids":["10366450"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Yeast two-hybrid screen, interaction domain mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid with domain mapping, single lab, no reconstitution","pmids":["10660610"],"is_preprint":false},{"year":2001,"finding":"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.","method":"In vitro APC activity assays, binding assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitin ligase activity assays, replicated by independent lab in same year (PMID:11459825)","pmids":["11459826"],"is_preprint":false},{"year":2001,"finding":"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.","method":"In vitro APC activity assays, binding assays, Xenopus egg extract reconstitution","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with APC activity assay, independently replicated (PMID:11459826)","pmids":["11459825"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Co-immunoprecipitation, transfection assays, mitotic checkpoint assays","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with functional checkpoint assay, single lab","pmids":["11717438"],"is_preprint":false},{"year":2003,"finding":"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).","method":"Protein purification, biochemical transferase assays, kinetic analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assay with purified proteins, single lab; negative finding is rigorously established","pmids":["12529368"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Protein copurification, binding assays, domain mapping","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical copurification with domain mapping, single lab","pmids":["16227619"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Co-immunoprecipitation, kinase assays, reporter gene assays, loss-of-function","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal co-IP and functional reporter assay, single lab","pmids":["17296730"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Cyclin B1 ubiquitination assay, synchronized cell infection, siRNA knockdown, in vivo rabbit intestinal model","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitination assay combined with cell-based and in vivo functional experiments","pmids":["17719540"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Yeast two-hybrid, endogenous co-immunoprecipitation, confocal co-localization, cell cycle fractionation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — endogenous co-IP and co-localization with domain mapping, single lab","pmids":["19753112"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Yeast two-hybrid, co-immunoprecipitation, EMSA, TOPFLASH reporter assay, chromatin immunoprecipitation, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (co-IP, EMSA, ChIP, reporter), single lab","pmids":["19443654"],"is_preprint":false},{"year":2010,"finding":"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.","method":"X-ray crystallography, structural analysis, functional complementation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, single lab but multiple structural forms resolved","pmids":["20164194"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Binding assays, peptide competition, domain mapping","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vitro binding assays with domain mapping, single lab","pmids":["20088965"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Yeast two-hybrid, GST pull-down, endogenous co-immunoprecipitation, confocal microscopy, siRNA knockdown","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — endogenous co-IP and co-localization with functional spindle phenotype, single lab","pmids":["21152103"],"is_preprint":false},{"year":2012,"finding":"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.","method":"X-ray crystallography, structural analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of ternary complex, reveals mechanism of polymerase switching","pmids":["22859296"],"is_preprint":false},{"year":2012,"finding":"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.","method":"NMR spectroscopy, binding interface mapping","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure-based interface mapping, single lab but rigorous method","pmids":["22828282"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, overexpression","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays (co-IP, ubiquitination, degradation) in single lab","pmids":["23287467"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Positional cloning, transgenic rescue, protein interaction assay, cell cycle analysis, gamma-H2AX foci","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse genetics with molecular mechanistic validation and transgenic rescue","pmids":["24356953"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Knockout mouse phenotyping, immunofluorescence, co-immunoprecipitation, transfection of fibroblasts with interaction assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with multiple molecular mechanism validations (co-IP with G9a/GLP, CDK1 inhibition assay)","pmids":["24009519"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Knockout mouse generation, embryo analysis, apoptosis assays, immunostaining","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — complete KO mouse with detailed developmental phenotyping, independent replication of PGC requirement (PMID:24009519)","pmids":["23463509"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Genetic KO/knockdown in mouse and human cells, resection assays, HR assays, PARPi sensitivity assays, chromatin recruitment epistasis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, mouse and human cells, epistasis confirmed, independently replicated (PMID:25799990)","pmids":["25799992"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Functional genetic screening, knockdown, telomere overhang assays, immunofluorescence, class switch recombination assays, epistasis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, genetic epistasis, independently replicated (PMID:25799992)","pmids":["25799990"],"is_preprint":false},{"year":2015,"finding":"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.","method":"In vivo co-immunoprecipitation, mutagenesis, functional complementation in REV7-/- cells","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis with functional complementation in KO cell line, two binding sites validated","pmids":["25567983"],"is_preprint":false},{"year":2015,"finding":"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.","method":"siRNA knockdown, live cell imaging, spindle assembly analysis, co-immunoprecipitation","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — knockdown with functional phenotype and co-IP, single lab; negative SAC finding is mechanistically informative","pmids":["26697843"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Patient cell analysis, WT rescue, CRISPR/Cas9 KO, chromosome break assays, G2/M accumulation, γH2AX foci","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic identification with rescue and CRISPR validation, multiple orthogonal phenotypic readouts","pmids":["27500492"],"is_preprint":false},{"year":2017,"finding":"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.","method":"X-ray crystallography in two crystal forms, structure-based interaction analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with two crystal forms and structure-based mutagenesis, single lab","pmids":["28887307"],"is_preprint":false},{"year":2017,"finding":"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).","method":"Protein degradation assays, mutagenesis of destruction box, co-immunoprecipitation, colocalization, shRNA knockdown","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical degradation assays with mutagenesis and co-IP, single lab","pmids":["28440919"],"is_preprint":false},{"year":2018,"finding":"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.","method":"IP-mass spectrometry, co-immunoprecipitation, overexpression/knockdown, ubiquitination assays, p38 inhibitor","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS with mechanistic follow-up using ubiquitination assays and pathway inhibitor, single lab","pmids":["29360267"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Genetic mouse models, mass spectrometry, co-immunoprecipitation, CSR assays, epistasis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — discovery of shieldin complex with MS, genetic mouse models, multiple orthogonal functional assays; landmark study","pmids":["30046110"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Mass spectrometry proteomics, co-immunoprecipitation, knockdown, CSR assays, resection assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-based interactome with functional validation, multiple orthogonal methods, consistent with PMID:30046110","pmids":["30154076"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Proteomics, co-immunoprecipitation, siRNA knockdown, clonogenic survival assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — proteomics with functional follow-up, single lab","pmids":["29789392"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Chromatin fractionation, co-immunoprecipitation, immunofluorescence, cell cycle analysis","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromatin recruitment assays with mechanistic epistasis, single lab, multiple methods","pmids":["29160738"],"is_preprint":false},{"year":2018,"finding":"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.","method":"In vitro binding assays, structural analysis, functional complementation in Rev7-/- cells","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro structural and biochemical analysis combined with functional KO complementation","pmids":["30111544"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Single-cell microscopy resection assay in S. pombe, genetic epistasis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel single-cell assay with genetic epistasis, single lab, ortholog study in S. pombe","pmids":["29697047"],"is_preprint":false},{"year":2019,"finding":"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.","method":"X-ray crystallography (2.00-2.35 Å resolution), biochemical binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with biochemical validation of nucleotide-state preference, single lab","pmids":["31484720"],"is_preprint":false},{"year":2019,"finding":"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.","method":"X-ray crystallography, binding kinetics analysis, in vitro and in vivo binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with kinetics and mutagenesis validation, single lab","pmids":["31796627"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Biochemical conformational assays, co-immunoprecipitation, genetic KO, PARPi resistance assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical conformational assay with genetic and functional validation, multiple orthogonal methods","pmids":["31915374"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, chromatin fractionation, PARPi sensitivity assays, overexpression/knockdown","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays and functional validation, single lab","pmids":["33051298"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Conditional KO mouse models (B cell specific), genetic epistasis (AID/REV7 double KO rescue), cell death assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with genetic epistasis using double KO rescue, mechanistic pathway placement","pmids":["32499490"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, mutagenesis, NHEJ assays, CSR assays, interaction kinetics","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple biochemical assays with mutagenesis and functional validation, consistent with prior structural and biochemical data","pmids":["34521823"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, knockdown, resection assays, HR assays, PARPi sensitivity","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding with mechanistic functional assays, single lab","pmids":["36044844"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Single-molecule DNA fiber assays, genetic epistasis, MRE11 inhibition, SMARD analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — single-molecule assays with genetic epistasis, multiple orthogonal methods revealing shieldin-independent mechanism","pmids":["36075897"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Mutagenesis of MAD2L2, co-immunoprecipitation in human cell line","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mutagenesis with co-IP, single lab, mechanistic binding mapping","pmids":["32811646"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, phosphorylation assays, knockdown/overexpression","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with functional phosphorylation assay, single lab, single publication","pmids":["38557443"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, knockdown/overexpression rescue experiments, xenograft","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with epistasis rescue experiments, single lab","pmids":["38515112"],"is_preprint":false}],"current_model":"MAD2L2 (REV7) is a multifunctional HORMA-domain adaptor protein that operates in at least three mechanistic contexts: (1) as the non-catalytic subunit of DNA polymerase zeta (bound to REV3L via two conserved REV7-binding motifs and to REV1 via a distinct interface), enabling translesion synthesis and replication fork protection in a REV1/REV3L-dependent manner; (2) as the central component of the shieldin complex (with SHLD1, SHLD2, SHLD3), where it inhibits 5' DSB end resection downstream of the 53BP1-RIF1 axis to promote NHEJ over HR—a function regulated by TRIP13-catalyzed open-to-closed conformational switching and by p31comet; and (3) as an inhibitor of both CDH1-APC and CDC20-APC in mitotic cell cycle control; additionally, REV7 interacts with RAN, CLTA, Elk-1/JNK, TCF4, p53, and various other proteins, placing it as a broad-spectrum signaling hub whose multivalent HORMA seatbelt domain accommodates structurally diverse ligands."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1985,"claim":"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","pmids":["3897794","7871890"],"confidence":"High","gaps":["No biochemical activity assigned","Mammalian ortholog and protein partners unknown"]},{"year":1999,"claim":"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","pmids":["10366450"],"confidence":"Medium","gaps":["No functional mechanism established beyond homology","Relationship to MAD2L1 function unresolved"]},{"year":2001,"claim":"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","pmids":["11459826","11459825"],"confidence":"High","gaps":["Physiological context of APC inhibition vs. spindle checkpoint unclear","Structural basis of activator binding not defined"]},{"year":2000,"claim":"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","pmids":["10660610"],"confidence":"Medium","gaps":["No reconstitution of pol zeta activity","REV1 interaction not yet defined"]},{"year":2007,"claim":"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","pmids":["17719540","17296730"],"confidence":"High","gaps":["Structural basis of IpaB binding not yet resolved","Breadth of REV7 signaling functions unclear"]},{"year":2012,"claim":"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","pmids":["20164194","22859296","22828282","20088965"],"confidence":"High","gaps":["Catalytic mechanism of the assembled pol zeta not addressed","Conformational regulation of REV7 not yet known"]},{"year":2013,"claim":"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","pmids":["24356953","24009519","23463509"],"confidence":"High","gaps":["Mechanism of chromatin-state transitions partially defined","Tissue specificity of phenotypes not fully explained"]},{"year":2015,"claim":"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","pmids":["25799992","25799990","25567983"],"confidence":"High","gaps":["Identity of effector subunits enforcing resection block not yet known","How a single protein toggles between TLS and end-protection unresolved"]},{"year":2016,"claim":"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","pmids":["27500492"],"confidence":"High","gaps":["Which REV7 function (TLS vs. shieldin) underlies FA not fully dissected"]},{"year":2018,"claim":"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","pmids":["30046110","30154076","29789392","29160738","30111544","29697047"],"confidence":"High","gaps":["How shieldin physically blocks nucleases at the DNA end not defined","Quantitative interplay of dimerization across complexes unclear"]},{"year":2020,"claim":"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","pmids":["31915374","33051298","32499490"],"confidence":"High","gaps":["Upstream signals controlling TRIP13/p31comet activity unknown","How closed/open ratio is spatially regulated at lesions unclear"]},{"year":2019,"claim":"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","pmids":["31484720","31796627","28887307"],"confidence":"High","gaps":["Physiological consequences of RAN/CAMP binding not fully established","Competition hierarchy among seatbelt ligands in cells unclear"]},{"year":2022,"claim":"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","pmids":["36075897","36044844","32811646"],"confidence":"High","gaps":["Mechanism of fork protection at the molecular level not resolved","In vivo relevance of CHAMP1 competition not established"]},{"year":2024,"claim":"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","pmids":["38557443","38515112"],"confidence":"Medium","gaps":["Single-lab co-IP without reciprocal structural validation","Direct vs. indirect effects on p53 phosphorylation not separated"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model of partner-selection regulation","Upstream determinants of conformational state in vivo unknown","Quantitative competition among seatbelt ligands uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[13,16,30,34,41]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5,10,38]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[22,23,28,33]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[22,23]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[22,23,30,31,43]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[13,24,43]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,5,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[26]}],"complexes":["DNA polymerase zeta (REV3L-REV7)","shieldin (REV7-SHLD1-SHLD2-SHLD3)","REV1/pol zeta TLS complex"],"partners":["REV3L","REV1","SHLD3","SHLD2","TRIP13","RAN","CHAMP1","53BP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UI95","full_name":"Mitotic spindle assembly checkpoint protein MAD2B","aliases":["Mitotic arrest deficient 2-like protein 2","MAD2-like protein 2","REV7 homolog","hREV7"],"length_aa":211,"mass_kda":24.3,"function":"Adapter protein able to interact with different proteins and involved in different biological processes (PubMed:11459825, PubMed:11459826, PubMed:17296730, PubMed:17719540, PubMed:19443654, PubMed:29656893). Mediates the interaction between the error-prone DNA polymerase zeta catalytic subunit REV3L and the inserter polymerase REV1, thereby mediating the second polymerase switching in translesion DNA synthesis (PubMed:20164194, PubMed:23143872). Translesion DNA synthesis releases the replication blockade of replicative polymerases, stalled in presence of DNA lesions (PubMed:20164194). Component of the shieldin complex, which plays an important role in repair of DNA double-stranded breaks (DSBs) (PubMed:29656893). During G1 and S phase of the cell cycle, the complex functions downstream of TP53BP1 to promote non-homologous end joining (NHEJ) and suppress DNA end resection (PubMed:29656893). Mediates various NHEJ-dependent processes including immunoglobulin class-switch recombination, and fusion of unprotected telomeres (PubMed:29656893). May also regulate another aspect of cellular response to DNA damage through regulation of the JNK-mediated phosphorylation and activation of the transcriptional activator ELK1 (PubMed:17296730). Inhibits the FZR1- and probably CDC20-mediated activation of the anaphase promoting complex APC thereby regulating progression through the cell cycle (PubMed:11459825, PubMed:17719540). Regulates TCF7L2-mediated gene transcription and may play a role in epithelial-mesenchymal transdifferentiation (PubMed:19443654)","subcellular_location":"Nucleus; Cytoplasm, cytoskeleton, spindle; Cytoplasm; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q9UI95/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MAD2L2","classification":"Common Essential","n_dependent_lines":1103,"n_total_lines":1208,"dependency_fraction":0.9130794701986755},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAD2L2","total_profiled":1310},"omim":[{"mim_id":"618030","title":"SHIELD COMPLEX, SUBUNIT 3; SHLD3","url":"https://www.omim.org/entry/618030"},{"mim_id":"618029","title":"SHIELD COMPLEX, SUBUNIT 2; SHLD2","url":"https://www.omim.org/entry/618029"},{"mim_id":"618028","title":"SHIELD COMPLEX, SUBUNIT 1; SHLD1","url":"https://www.omim.org/entry/618028"},{"mim_id":"617243","title":"FANCONI ANEMIA, COMPLEMENTATION GROUP V; FANCV","url":"https://www.omim.org/entry/617243"},{"mim_id":"616327","title":"CHROMOSOME ALIGNMENT-MAINTAINING PHOSPHOPROTEIN 1; CHAMP1","url":"https://www.omim.org/entry/616327"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAD2L2"},"hgnc":{"alias_symbol":["MAD2B","REV7","POLZ2","FANCV"],"prev_symbol":[]},"alphafold":{"accession":"Q9UI95","domains":[{"cath_id":"3.30.900.10","chopping":"10-205","consensus_level":"high","plddt":92.9418,"start":10,"end":205}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI95","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI95-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI95-F1-predicted_aligned_error_v6.png","plddt_mean":90.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAD2L2","jax_strain_url":"https://www.jax.org/strain/search?query=MAD2L2"},"sequence":{"accession":"Q9UI95","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UI95.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UI95/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI95"}},"corpus_meta":[{"pmid":"25799992","id":"PMC_25799992","title":"REV7 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\"finding\": \"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.\",\n      \"method\": \"Genetic mutant screen, UV survival and reversion assays, epistasis analysis\",\n      \"journal\": \"Molecular & general genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — foundational genetic epistasis in yeast, replicated across multiple alleles\",\n      \"pmids\": [\"3897794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Yeast REV7 gene was cloned and sequenced; its function is required for DNA damage-induced mutagenesis but is not essential for viability.\",\n      \"method\": \"Complementation cloning, sequence analysis\",\n      \"journal\": \"Yeast\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic complementation, single lab, cloning and functional verification\",\n      \"pmids\": [\"7871890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human MAD2B (MAD2L2) gene was isolated and characterized as homologous to the spindle checkpoint gene MAD2 (MAD2L1); chromosomal localization was determined (chromosome 1p36).\",\n      \"method\": \"Gene isolation, sequence homology analysis, chromosomal localization, tumor mutation screening\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gene characterization, single lab, no functional mechanism established beyond homology identification\",\n      \"pmids\": [\"10366450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, interaction domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid with domain mapping, single lab, no reconstitution\",\n      \"pmids\": [\"10660610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro APC activity assays, binding assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitin ligase activity assays, replicated by independent lab in same year (PMID:11459825)\",\n      \"pmids\": [\"11459826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro APC activity assays, binding assays, Xenopus egg extract reconstitution\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with APC activity assay, independently replicated (PMID:11459826)\",\n      \"pmids\": [\"11459825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, transfection assays, mitotic checkpoint assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with functional checkpoint assay, single lab\",\n      \"pmids\": [\"11717438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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).\",\n      \"method\": \"Protein purification, biochemical transferase assays, kinetic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assay with purified proteins, single lab; negative finding is rigorously established\",\n      \"pmids\": [\"12529368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Protein copurification, binding assays, domain mapping\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical copurification with domain mapping, single lab\",\n      \"pmids\": [\"16227619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, kinase assays, reporter gene assays, loss-of-function\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal co-IP and functional reporter assay, single lab\",\n      \"pmids\": [\"17296730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Cyclin B1 ubiquitination assay, synchronized cell infection, siRNA knockdown, in vivo rabbit intestinal model\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitination assay combined with cell-based and in vivo functional experiments\",\n      \"pmids\": [\"17719540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, endogenous co-immunoprecipitation, confocal co-localization, cell cycle fractionation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — endogenous co-IP and co-localization with domain mapping, single lab\",\n      \"pmids\": [\"19753112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, EMSA, TOPFLASH reporter assay, chromatin immunoprecipitation, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (co-IP, EMSA, ChIP, reporter), single lab\",\n      \"pmids\": [\"19443654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, structural analysis, functional complementation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, single lab but multiple structural forms resolved\",\n      \"pmids\": [\"20164194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Binding assays, peptide competition, domain mapping\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vitro binding assays with domain mapping, single lab\",\n      \"pmids\": [\"20088965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, endogenous co-immunoprecipitation, confocal microscopy, siRNA knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — endogenous co-IP and co-localization with functional spindle phenotype, single lab\",\n      \"pmids\": [\"21152103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, structural analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of ternary complex, reveals mechanism of polymerase switching\",\n      \"pmids\": [\"22859296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"NMR spectroscopy, binding interface mapping\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure-based interface mapping, single lab but rigorous method\",\n      \"pmids\": [\"22828282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, overexpression\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays (co-IP, ubiquitination, degradation) in single lab\",\n      \"pmids\": [\"23287467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Positional cloning, transgenic rescue, protein interaction assay, cell cycle analysis, gamma-H2AX foci\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse genetics with molecular mechanistic validation and transgenic rescue\",\n      \"pmids\": [\"24356953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Knockout mouse phenotyping, immunofluorescence, co-immunoprecipitation, transfection of fibroblasts with interaction assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with multiple molecular mechanism validations (co-IP with G9a/GLP, CDK1 inhibition assay)\",\n      \"pmids\": [\"24009519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Knockout mouse generation, embryo analysis, apoptosis assays, immunostaining\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complete KO mouse with detailed developmental phenotyping, independent replication of PGC requirement (PMID:24009519)\",\n      \"pmids\": [\"23463509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic KO/knockdown in mouse and human cells, resection assays, HR assays, PARPi sensitivity assays, chromatin recruitment epistasis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, mouse and human cells, epistasis confirmed, independently replicated (PMID:25799990)\",\n      \"pmids\": [\"25799992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Functional genetic screening, knockdown, telomere overhang assays, immunofluorescence, class switch recombination assays, epistasis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, genetic epistasis, independently replicated (PMID:25799992)\",\n      \"pmids\": [\"25799990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo co-immunoprecipitation, mutagenesis, functional complementation in REV7-/- cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis with functional complementation in KO cell line, two binding sites validated\",\n      \"pmids\": [\"25567983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, live cell imaging, spindle assembly analysis, co-immunoprecipitation\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — knockdown with functional phenotype and co-IP, single lab; negative SAC finding is mechanistically informative\",\n      \"pmids\": [\"26697843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Patient cell analysis, WT rescue, CRISPR/Cas9 KO, chromosome break assays, G2/M accumulation, γH2AX foci\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic identification with rescue and CRISPR validation, multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"27500492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography in two crystal forms, structure-based interaction analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with two crystal forms and structure-based mutagenesis, single lab\",\n      \"pmids\": [\"28887307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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).\",\n      \"method\": \"Protein degradation assays, mutagenesis of destruction box, co-immunoprecipitation, colocalization, shRNA knockdown\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical degradation assays with mutagenesis and co-IP, single lab\",\n      \"pmids\": [\"28440919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"IP-mass spectrometry, co-immunoprecipitation, overexpression/knockdown, ubiquitination assays, p38 inhibitor\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS with mechanistic follow-up using ubiquitination assays and pathway inhibitor, single lab\",\n      \"pmids\": [\"29360267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic mouse models, mass spectrometry, co-immunoprecipitation, CSR assays, epistasis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — discovery of shieldin complex with MS, genetic mouse models, multiple orthogonal functional assays; landmark study\",\n      \"pmids\": [\"30046110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry proteomics, co-immunoprecipitation, knockdown, CSR assays, resection assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-based interactome with functional validation, multiple orthogonal methods, consistent with PMID:30046110\",\n      \"pmids\": [\"30154076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomics, co-immunoprecipitation, siRNA knockdown, clonogenic survival assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — proteomics with functional follow-up, single lab\",\n      \"pmids\": [\"29789392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Chromatin fractionation, co-immunoprecipitation, immunofluorescence, cell cycle analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromatin recruitment assays with mechanistic epistasis, single lab, multiple methods\",\n      \"pmids\": [\"29160738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro binding assays, structural analysis, functional complementation in Rev7-/- cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro structural and biochemical analysis combined with functional KO complementation\",\n      \"pmids\": [\"30111544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Single-cell microscopy resection assay in S. pombe, genetic epistasis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel single-cell assay with genetic epistasis, single lab, ortholog study in S. pombe\",\n      \"pmids\": [\"29697047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography (2.00-2.35 Å resolution), biochemical binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with biochemical validation of nucleotide-state preference, single lab\",\n      \"pmids\": [\"31484720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, binding kinetics analysis, in vitro and in vivo binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with kinetics and mutagenesis validation, single lab\",\n      \"pmids\": [\"31796627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical conformational assays, co-immunoprecipitation, genetic KO, PARPi resistance assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical conformational assay with genetic and functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"31915374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, chromatin fractionation, PARPi sensitivity assays, overexpression/knockdown\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays and functional validation, single lab\",\n      \"pmids\": [\"33051298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional KO mouse models (B cell specific), genetic epistasis (AID/REV7 double KO rescue), cell death assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with genetic epistasis using double KO rescue, mechanistic pathway placement\",\n      \"pmids\": [\"32499490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis, NHEJ assays, CSR assays, interaction kinetics\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple biochemical assays with mutagenesis and functional validation, consistent with prior structural and biochemical data\",\n      \"pmids\": [\"34521823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, knockdown, resection assays, HR assays, PARPi sensitivity\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding with mechanistic functional assays, single lab\",\n      \"pmids\": [\"36044844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Single-molecule DNA fiber assays, genetic epistasis, MRE11 inhibition, SMARD analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — single-molecule assays with genetic epistasis, multiple orthogonal methods revealing shieldin-independent mechanism\",\n      \"pmids\": [\"36075897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Mutagenesis of MAD2L2, co-immunoprecipitation in human cell line\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mutagenesis with co-IP, single lab, mechanistic binding mapping\",\n      \"pmids\": [\"32811646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, knockdown/overexpression\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with functional phosphorylation assay, single lab, single publication\",\n      \"pmids\": [\"38557443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/overexpression rescue experiments, xenograft\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with epistasis rescue experiments, single lab\",\n      \"pmids\": [\"38515112\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAD2L2 (REV7) is a multifunctional HORMA-domain adaptor protein that operates in at least three mechanistic contexts: (1) as the non-catalytic subunit of DNA polymerase zeta (bound to REV3L via two conserved REV7-binding motifs and to REV1 via a distinct interface), enabling translesion synthesis and replication fork protection in a REV1/REV3L-dependent manner; (2) as the central component of the shieldin complex (with SHLD1, SHLD2, SHLD3), where it inhibits 5' DSB end resection downstream of the 53BP1-RIF1 axis to promote NHEJ over HR—a function regulated by TRIP13-catalyzed open-to-closed conformational switching and by p31comet; and (3) as an inhibitor of both CDH1-APC and CDC20-APC in mitotic cell cycle control; additionally, REV7 interacts with RAN, CLTA, Elk-1/JNK, TCF4, p53, and various other proteins, placing it as a broad-spectrum signaling hub whose multivalent HORMA seatbelt domain accommodates structurally diverse ligands.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#13, #27, #36]. 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 [#13, #16, #24, #34]; this activity underlies damage-induced mutagenesis and resistance to UV and crosslinking agents [#0, #24], and a point mutation (C70R) that severs the REV7–REV3 interaction abolishes damage tolerance and causes germ-cell loss and infertility [#19]. 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 [#22, #23, #30, #31, #33]. 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 [#37, #38, #39, #41, #42]. Independently of shieldin, REV7 protects and restarts stalled replication forks in a REV3L/REV1-dependent manner by limiting MRE11 resection [#43]. In mitotic control, MAD2L2 inhibits both CDH1-APC and CDC20-APC by binding the activators rather than the core APC [#4, #5], and biallelic inactivating REV7 mutations cause Fanconi anemia (REV7 = FANCV) [#26].\",\n  \"teleology\": [\n    {\n      \"year\": 1985,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast mutant screen with UV survival/reversion and RAD6 epistasis analysis\",\n      \"pmids\": [\"3897794\", \"7871890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No biochemical activity assigned\", \"Mammalian ortholog and protein partners unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified the human gene MAD2L2 as a MAD2 homolog, raising the question of whether it functioned in the spindle checkpoint or elsewhere.\",\n      \"evidence\": \"Gene isolation, homology analysis, and chromosomal mapping with tumor mutation screening\",\n      \"pmids\": [\"10366450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional mechanism established beyond homology\", \"Relationship to MAD2L1 function unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro APC ubiquitin-ligase and binding assays, Xenopus egg-extract reconstitution\",\n      \"pmids\": [\"11459826\", \"11459825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological context of APC inhibition vs. spindle checkpoint unclear\", \"Structural basis of activator binding not defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Connected human REV7 to translesion synthesis by demonstrating it binds the pol zeta catalytic subunit REV3, linking it to the yeast mutagenesis phenotype.\",\n      \"evidence\": \"Yeast two-hybrid screen with interaction domain mapping\",\n      \"pmids\": [\"10660610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstitution of pol zeta activity\", \"REV1 interaction not yet defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cyclin B1 ubiquitination assays, infection models, in vivo intestinal model, kinase and reporter assays\",\n      \"pmids\": [\"17719540\", \"17296730\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IpaB binding not yet resolved\", \"Breadth of REV7 signaling functions unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Crystal structures of REV7–REV3 and REV1-CTD–REV7–REV3 ternary complex; NMR interface mapping\",\n      \"pmids\": [\"20164194\", \"22859296\", \"22828282\", \"20088965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism of the assembled pol zeta not addressed\", \"Conformational regulation of REV7 not yet known\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Mouse positional cloning of the C70R mutation, transgenic rescue, knockouts, cell-cycle and γH2AX analyses\",\n      \"pmids\": [\"24356953\", \"24009519\", \"23463509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of chromatin-state transitions partially defined\", \"Tissue specificity of phenotypes not fully explained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genetic KO/knockdown in mouse and human cells, resection/HR assays, telomere fusion assays, chromatin recruitment epistasis\",\n      \"pmids\": [\"25799992\", \"25799990\", \"25567983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of effector subunits enforcing resection block not yet known\", \"How a single protein toggles between TLS and end-protection unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified REV7 as the Fanconi anemia gene FANCV, linking its loss to a defined human chromosome-instability disease.\",\n      \"evidence\": \"Patient-cell analysis, WT rescue, CRISPR/Cas9 KO, chromosome-break and γH2AX assays\",\n      \"pmids\": [\"27500492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which REV7 function (TLS vs. shieldin) underlies FA not fully dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Mouse genetics, MS interactomics, co-IP, CSR/resection assays, structural and biochemical dimerization analysis\",\n      \"pmids\": [\"30046110\", \"30154076\", \"29789392\", \"29160738\", \"30111544\", \"29697047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How shieldin physically blocks nucleases at the DNA end not defined\", \"Quantitative interplay of dimerization across complexes unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Biochemical conformational assays, co-IP, genetic KO, PARPi sensitivity, conditional B-cell KO with epistasis\",\n      \"pmids\": [\"31915374\", \"33051298\", \"32499490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling TRIP13/p31comet activity unknown\", \"How closed/open ratio is spatially regulated at lesions unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Multiple X-ray crystal structures with binding-kinetics and nucleotide-preference assays\",\n      \"pmids\": [\"31484720\", \"31796627\", \"28887307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequences of RAN/CAMP binding not fully established\", \"Competition hierarchy among seatbelt ligands in cells unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Distinguished a shieldin-independent fork-protection role and identified competing seatbelt ligands (CHAMP1) that rebalance repair choice, broadening REV7's genome-maintenance reach.\",\n      \"evidence\": \"DNA fiber and SMARD assays with REV3L/REV1/MRE11 epistasis; co-IP, resection/HR and PARPi assays for CHAMP1; APC activator binding mapping\",\n      \"pmids\": [\"36075897\", \"36044844\", \"32811646\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of fork protection at the molecular level not resolved\", \"In vivo relevance of CHAMP1 competition not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended REV7's signaling roles by linking it to p53 regulation and AURKB-dependent DDR, hinting at integration of repair with damage-response signaling.\",\n      \"evidence\": \"Co-IP, phosphorylation assays, knockdown/overexpression rescue, xenografts\",\n      \"pmids\": [\"38557443\", \"38515112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab co-IP without reciprocal structural validation\", \"Direct vs. indirect effects on p53 phosphorylation not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model of partner-selection regulation\", \"Upstream determinants of conformational state in vivo unknown\", \"Quantitative competition among seatbelt ligands uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [13, 16, 30, 34, 41]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5, 10, 38]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [22, 23, 28, 33]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [22, 23]},\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [11, 15, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [22, 23, 30, 31, 43]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [13, 24, 43]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 5, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"complexes\": [\n      \"DNA polymerase zeta (REV3L-REV7)\",\n      \"shieldin (REV7-SHLD1-SHLD2-SHLD3)\",\n      \"REV1/pol zeta TLS complex\"\n    ],\n    \"partners\": [\n      \"REV3L\",\n      \"REV1\",\n      \"SHLD3\",\n      \"SHLD2\",\n      \"TRIP13\",\n      \"RAN\",\n      \"CHAMP1\",\n      \"53BP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}