Affinage

MSH2

DNA mismatch repair protein Msh2 · UniProt P43246

Length
934 aa
Mass
104.7 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MSH2 is the obligate, shared subunit of the eukaryotic mismatch-recognition heterodimers that initiate DNA mismatch repair (MMR): a MutS homolog whose heterologous expression confers a dominant mutator phenotype (PMID:8252616), it partners with MSH6 to recognize base-base mispairs and with MSH3 to recognize insertion/deletion loops (PMID:8600025), and these complexes nucleate a ternary repair assembly with the MLH1-PMS1 heterodimer at heteroduplex DNA (PMID:8066446, PMID:9368761). Loading is coordinated with replication through PCNA, which forms a stable ternary complex with MutSα on homoduplex DNA; mismatch binding disrupts the PCNA interaction and ATP restores it, supporting transfer of MutSα from PCNA onto the mispair (PMID:12435741), after which PCNA and MutSα activate the latent MLH1-PMS1 endonuclease and license Exo1-dependent or Exo1-independent excision (PMID:24981171); Exo1 is recruited directly through SHIP-box peptides that dock on an MSH2 interface disrupted by the msh2-M470I mutation (PMID:30061603). ATP-driven conformational cycling within the MSH2-MSH6 ATPase domains couples nucleotide binding to mismatch recognition and downstream excision, as defined by separation-of-function mutants (G674A and the MSH6 T1219D coupling mutant) that retain mismatch binding but fail to support repair (PMID:22277660). Beyond repair, MSH2 is a damage-signaling platform: it associates with ATR to drive Chk1 and SMC1 phosphorylation and S-phase checkpoint activation after methylation damage (PMID:14657349) and is required for genotoxin-induced, largely p53-dependent apoptosis (PMID:10097137); this signaling function is genetically separable from repair, since the G674A ATPase mutant abolishes MMR yet preserves apoptotic tumor suppression (PMID:14744764). MSH2-MSH3 also promotes trinucleotide repeat expansion, binding CAG hairpins to inhibit its own ATPase (PMID:16025128) and stimulating DNA polymerase β during base excision repair to convert repeat instability toward expansion (PMID:27546332), a process requiring a functional MSH2 ATPase domain in vivo (PMID:19436705). MSH2 abundance is set by opposing enzymes—HDAC6-mediated deacetylation/ubiquitination promoting degradation (PMID:24882211) and OTUB1-mediated protection from ubiquitination (PMID:33640455). Independent of catalytic repair, MSH2 carries a non-canonical epigenomic role, binding super-enhancers via MSH6 and SMARCA4/BRG1 to maintain chromatin architecture and cell adhesion gene expression (PMID:35583999).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1993 High

    Established MSH2 as the human counterpart of bacterial MutS and a bona fide mismatch repair factor, defining the gene's foundational function.

    Evidence Heterologous expression of hMSH2 in E. coli producing a dominant mutator phenotype, with gene mapping

    PMID:8252616

    Open questions at the time
    • Did not define which mammalian partners MSH2 uses
    • No direct demonstration of mismatch binding by the human protein in this study
  2. 1996 High

    Resolved that MSH2 is a shared subunit forming two distinct heterodimers with division of substrate labor, explaining how a single protein covers both base-base and indel mispairs.

    Evidence Yeast mutation-rate epistasis across msh2/msh3/msh6 combinations plus MSH2-MSH3/MSH6 physical interaction assays

    PMID:8600025

    Open questions at the time
    • Did not establish the structural basis of differential substrate recognition
    • Human reconstitution not shown here
  3. 1997 High

    Connected mismatch recognition to downstream MutL recruitment by showing MSH2-heteroduplex complexes form a ternary assembly with MLH1-PMS1 and that MLH1-PMS1 enhances MSH2-MSH3 mismatch binding.

    Evidence In vitro ternary complex formation on G-T heteroduplex DNA and gel-shift binding enhancement with purified MLH1-PMS1

    PMID:8066446 PMID:9368761

    Open questions at the time
    • Order of events relative to replication not addressed
    • Endonuclease activation step not yet defined
  4. 1997 Medium

    Provided a biochemical basis for MSH2 involvement in trinucleotide repeat instability by showing structure-specific binding to slipped-strand repeat DNA.

    Evidence EMSA with purified MSH2 on synthetic CTG/CAG slipped-strand substrates

    PMID:9215683

    Open questions at the time
    • Single lab, single method (EMSA)
    • Functional consequence for expansion not tested here
    • MSH2-MSH3 vs MSH2 alone not resolved
  5. 2002 High

    Defined the PCNA hand-off mechanism that times MutSα loading to replication, showing mismatch binding releases PCNA and ATP restores it.

    Evidence Gel filtration and pull-down ternary complex assays comparing homoduplex versus G/T heteroduplex with ATP addition

    PMID:12435741

    Open questions at the time
    • Did not show how released PCNA later activates the endonuclease
    • In vivo timing not established
  6. 2002 Medium

    Linked MSH2 to broader S-phase genome surveillance by placing it in S-phase nuclear foci with p53 and recombination factors.

    Evidence Immunofluorescence colocalization and nuclear co-immunoprecipitation in synchronized cells

    PMID:12101417

    Open questions at the time
    • Correlative localization without direct functional dissection
    • Whether MSH2 acts in homologous recombination not mechanistically shown
  7. 2003 High

    Identified MSH2 as a direct damage-signaling platform for the ATR-Chk1 axis, separating signaling from repair catalysis.

    Evidence Endogenous MSH2-ATR co-IP, siRNA knockdown, and Chk1/SMC1 phosphorylation and S-phase checkpoint assays after MNNG

    PMID:14657349

    Open questions at the time
    • Direct kinase-substrate scaffolding mechanism not resolved
    • Stoichiometry and dynamics of the MSH2-ATR module unknown
  8. 2004 High

    Genetically uncoupled MSH2's apoptotic/damage-signaling tumor suppressor role from its repair function using a separation-of-function ATPase mutant.

    Evidence Msh2-G674A knock-in mouse with tumor, chemotherapy-response, and apoptosis readouts

    PMID:14744764

    Open questions at the time
    • Molecular reason the ATPase mutant retains signaling not defined
    • Did not identify the signaling effector distinct from repair
  9. 2012 High

    Provided the biochemical mechanism for the repair/signaling split, showing ATPase and nucleotide-coupling mutants retain mismatch binding but stall before excision and act dominantly.

    Evidence In vitro MMR, kinetic DNA binding, ATPase, and excision assays with purified MSH2(G674A) and MSH6(T1219D) proteins

    PMID:22277660

    Open questions at the time
    • Did not test apoptotic signaling output of these mutants biochemically
    • Structural snapshot of the stalled intermediate not provided
  10. 2014 High

    Completed the catalytic logic of initiation by showing PCNA plus MutSα activate the MLH1-PMS1 endonuclease for Exo1-independent repair.

    Evidence Yeast PCNA mutant screen with MMR assays, Mlh1-Pms1 focus accumulation, and epistasis with msh6 PCNA-binding mutants

    PMID:24981171

    Open questions at the time
    • Mechanism of nick placement directionality not fully defined
    • Human reconstitution not shown in this study
  11. 2018 High

    Defined the direct molecular interface by which MSH2 tethers the nuclease Exo1 via SHIP-box peptides.

    Evidence Yeast genetics, in vitro MMR with SHIP peptide competition, and msh2-M470I interface mutagenesis

    PMID:30061603

    Open questions at the time
    • Atomic structure of the SHIP-MSH2 interface not solved here
    • Generality across other SHIP-box proteins only partially explored
  12. 2016 High

    Mechanistically explained how MSH2-MSH3 drives repeat expansion by acting within base excision repair to stimulate pol β and bias outcomes toward expansion.

    Evidence In vitro BER reconstitution with purified MSH2-MSH3 and pol β, flap-formation and deletion/expansion assays on defined substrates

    PMID:16025128 PMID:19436705 PMID:27546332

    Open questions at the time
    • In vivo coordination between BER and MMR pathways at repeats not resolved
    • Tissue-specific determinants of expansion not addressed
  13. 2021 High

    Established that MSH2 protein levels, and thereby repair capacity and drug response, are set by opposing ubiquitin-pathway enzymes.

    Evidence HDAC6 deacetylation/ubiquitination and OTUB1 deubiquitination assays with cellular MMR activity, mutation frequency, and MNNG/cisplatin sensitivity readouts

    PMID:24882211 PMID:33640455

    Open questions at the time
    • E3 ligase responsible for MSH2 ubiquitination not pinpointed
    • Crosstalk between acetylation and ubiquitination signals not fully mapped
  14. 2022 High

    Revealed a repair-independent epigenomic function in which MSH2 maintains super-enhancer chromatin architecture and cell adhesion gene expression.

    Evidence CRISPR-MS, genome-wide CRISPR screen, ChIP-seq, Hi-C, and rescue with catalytic-dead MSH2 in gastric cancer models

    PMID:35583999

    Open questions at the time
    • How MSH2 is targeted to specific super-enhancers not fully defined
    • Whether this role exists outside gastric cancer not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MSH2's repair, ATR-dependent signaling, repeat-expansion, and chromatin functions are partitioned and regulated within a single cell remains unresolved.
  • No unified structural model linking ATPase conformational states to the choice between repair, signaling, and chromatin roles
  • The E3 ligase and full regulatory network controlling MSH2 stability are incomplete
  • The recruitment determinants directing MSH2 to super-enhancers versus mismatches are unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140657 ATP-dependent activity 4 GO:0016787 hydrolase activity 3 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 1 GO:0005654 nucleoplasm 1
Pathway
R-HSA-73894 DNA Repair 6 R-HSA-1643685 Disease 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-4839726 Chromatin organization 1
Partners
ATREXO1MLH1MSH3MSH6PCNAPMS1SMARCA4
Complex memberships
MutSα (MSH2-MSH6)MutSβ (MSH2-MSH3)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Human MSH2 (hMSH2) is a homolog of bacterial MutS and yeast MSH proteins. Expression of hMSH2 in E. coli causes a dominant mutator phenotype, consistent with interference with the normal bacterial mismatch repair pathway, establishing MSH2 as a mismatch repair factor. Heterologous expression in E. coli with mutator phenotype readout; gene mapping Cell High 8252616
1994 Yeast MSH2, MLH1, and PMS1 form a ternary complex during mismatch repair initiation: MLH1 and PMS1 physically associate as a heterodimer and together bind an MSH2-heteroduplex complex containing a G-T mismatch. Physical interaction/co-binding assay; in vitro ternary complex formation with G-T mismatch-containing heteroduplex DNA Science High 8066446
1996 S. cerevisiae MSH2 operates via two mismatch repair pathways: one recognizing single-base mispairs requiring MSH2-MSH6, and a second recognizing insertion/deletion mispairs requiring MSH2-MSH3 or MSH2-MSH6. MSH2 physically interacts with both MSH3 and MSH6 to form distinct heterodimers. Mutation rate measurement across msh2/msh3/msh6 combinations; physical interaction studies between MSH2 and MSH3/MSH6 Genes & development High 8600025
1997 Human MSH2 protein binds to slipped-strand DNA structures (S-DNA and SI-DNA) formed from trinucleotide repeat sequences (CTG/CAG) in a structure-specific and length-dependent manner, with preferential binding to looped-out CAG repeat sequences. Band-shift (EMSA) assay with purified MSH2 protein and synthetic slipped-strand DNA substrates Human molecular genetics Medium 9215683
1997 The yeast MLH1-PMS1 heterodimer, by itself showing no affinity for mismatched DNA, greatly enhances the mismatch binding ability of MSH2-MSH3 upon interaction. Purification of MLH1-PMS1 heterodimer; gel mobility shift assay for mismatch DNA binding enhancement Current biology : CB High 9368761
1999 Msh2 is required for in vivo DNA damage-induced apoptosis in the intestinal epithelium in response to methylating agents (temozolomide, MNNG, cisplatin). This apoptotic response is primarily mediated through a p53-dependent pathway, with a secondary p53-independent delayed death also requiring Msh2. Msh2 null mouse model; in vivo apoptosis assay after genotoxic treatment; double-mutant analysis with p53 Proceedings of the National Academy of Sciences of the United States of America High 10097137
2000 MSH3 and MSH6, but not MSH2, contain N-terminal PCNA-interacting motifs. MSH2-MSH6 complex binds PCNA through MSH6's motif; alanine substitutions in the PCNA-binding motif of Msh6 or Msh3 elevated mutation rates. MSH3/MSH6 interaction with PCNA facilitates early steps in mismatch repair. Peptide binding to PCNA; alanine-substitution mutagenesis; mutation rate assay in yeast; mismatch repair inhibition assay in human cell extract The Journal of biological chemistry High 11005803
2002 MSH2-MSH6 (MutSα) forms a stable ternary complex with PCNA on homoduplex DNA, but MSH2-MSH6 binding to a heteroduplex (G/T mismatch) disrupts its interaction with PCNA. ATP addition restores PCNA binding, supporting a model where MSH2-MSH6 is transferred from PCNA to mispaired bases. Gel filtration and pull-down assays; ternary complex formation with PCNA, MSH2-MSH6, and homoduplex or heteroduplex DNA; ATP addition experiments The Journal of biological chemistry High 12435741
2002 MSH2 and MSH6 are phosphorylated in vitro by protein kinase C and casein kinase II (but not PKA), and are phosphorylated in vivo. Phosphorylation of MSH2 and MSH6 increases mismatch-binding activity of MutSα and is required for methylation-induced nuclear translocation of the MutSα repair complex. In vitro kinase assays; phosphatase treatment and kinase inhibitor experiments in cells; mismatch-binding assay; subcellular localization by fractionation Nucleic acids research Medium 11972333
2002 MSH2 and p53 co-localize in discrete nuclear foci during S phase, associate with recombination factors Rad50 and Rad51, and coexist in the same nuclear DNA-protein complexes during S phase, suggesting MSH2 plays a role in homologous recombination surveillance during DNA replication. Immunofluorescence colocalization; nuclear fractionation with co-immunoprecipitation; cell synchronization Oncogene Medium 12101417
2003 MSH2 interacts with the ATR kinase to form a signaling module that regulates phosphorylation of Chk1 and SMC1 in response to the DNA methylating agent MNNG. MSH2 and Rad17 are required for S-phase checkpoint activation to suppress DNA synthesis after MNNG treatment. Co-immunoprecipitation of endogenous MSH2 and ATR; siRNA knockdown; checkpoint assays; Chk1 and SMC1 phosphorylation assays Proceedings of the National Academy of Sciences of the United States of America High 14657349
2004 The DNA mismatch repair and DNA damage-induced apoptosis functions of Msh2 can be uncoupled: the G674A missense mutation in the conserved ATPase domain abrogates mismatch repair but retains DNA damage signaling for apoptosis. Msh2-mediated apoptosis is an independent tumor suppressor function. Knock-in mouse model (Msh2-G674A); tumor formation assay; chemotherapy response assay; apoptosis measurement Cancer research High 14744764
2004 ERCC1 physically interacts with MSH2 complexes in HeLa cell extracts. The minimum region in ERCC1 required for co-immunoprecipitation of MSH2 is the carboxyl-terminal domain (aa 184-260), overlapping with the XPF-binding domain. This interaction is involved cooperatively in resistance to cisplatin (CDDP) in mammalian cells; MSH2 deficiency suppresses ERCC1-dependent CDDP resistance in XPA-deficient cells. Co-immunoprecipitation from HeLa cell extracts; tagged ERCC1 in COS7 cells; siRNA knockdown; double mutant cell analysis (Xpa/Msh2 null cells) DNA repair Medium 14706347
2005 Human MSH2-MSH3 binds to CAG-hairpin DNA (an expansion intermediate); this binding inhibits the ATPase activity of MSH2-MSH3 and alters both ADP/ATP affinity and protein-DNA binding interfaces. Inhibition depends on A.A mispairs in the hairpin stem and the hairpin structure itself. This functional defect is proposed to misdirect repair and promote expansion. In vitro binding assay with purified MSH2-MSH3 and synthetic CAG-hairpin DNA; ATPase assay; nucleotide binding assay; mutagenesis of hairpin substrate Nature structural & molecular biology High 16025128
2006 The MSH2 DNA-binding domain I (msh2Δ1 deletion) shows a separation-of-function phenotype: it is dispensable for MSH2-MSH6-mediated MMR but is required for MSH2-MSH3-mediated MMR. Domain I of MSH2 contributes a non-specific DNA binding activity, while domain I of MSH3 contributes mismatch binding specificity. Yeast genetic assays (mutation rate); purified Msh2-Msh3 mispair binding analysis; domain deletion mutants Journal of molecular biology High 17157869
2007 Msh2-Msh3 exhibits robust binding to specific base-base mispairs (not only insertion/deletion loops), consistent with a role in repair of base-base mismatches and suppression of homology-mediated duplication/deletion mutations; this parallels Mlh1-Mlh3 mutant phenotypes. Yeast genetic assays (mutation rate, mutation spectrum at CAN1); purified Msh2-Msh3 mispair binding assay with DNA substrates derived from CAN1 Molecular and cellular biology High 17636021
2009 MSH2-MSH3 recognizes small DNA loops via a mechanism distinct from MSH2-MSH6. Upon loop binding, MSH2-MSH3 adopts a specific nucleotide signature (ADP in MSH2, empty MSH3 subunit). ATP binding and hydrolysis in MSH3 promotes ADP-ATP exchange in MSH2, generating a hydrolysis-independent ATP-MSH2-MSH3-ADP intermediate specific to loop-bound complex. Nucleotide binding assays with purified human MSH2-MSH3; ATPase assays; fluorescence-based nucleotide occupancy measurements on defined DNA substrates Nature structural & molecular biology High 19377479
2009 The MSH2 ATPase domain G674A mutation strongly reduces CTG repeat expansion and leads instead to contractions in DM1 transgenic mice (mimicking Msh2-null or Msh3-null deficiency), establishing that trinucleotide repeat expansion requires a functional MSH2 ATPase domain. Transgenic mouse cross; repeat instability analysis; protein level measurement PLoS genetics High 19436705
2009 MSH2 conformational change upon DNA binding is allosterically coupled to ATPase domain activity: in the absence of DNA, the clamp and lever domains of MSH6 and MSH2 open asymmetrically, and this opening is coupled to changes in the ATPase domains that diminish ATPase activity. Molecular dynamics simulation of human MSH2-MSH6 based on crystal structure; analysis of domain movements and ATPase domain changes Biophysical journal Low 19486659
2009 MSH2 deficiency in telomerase-deficient mice abolishes p21/p53-dependent cell-cycle arrest in response to short telomeres, eliminating the tumor suppressor activity of short telomeres and preventing degenerative pathologies by rescuing proliferative defects. Double knockout mice (MSH2(-/-) Terc(-/-)); tumor analysis; proliferation assay; p21/p53 pathway analysis Aging cell Medium 18986375
2012 Human MSH2(G674A)-MSH6 and MSH2-MSH6(T1219D) mutant proteins both fail to support mismatch repair in vitro while retaining mismatch recognition activity. MSH2(G674A)-MSH6 has a partial defect in nucleotide binding, while MSH2-MSH6(T1219D) fails to couple nucleotide binding and mismatch recognition. Both mutants remain bound at the mismatch and fail to promote excision, inhibiting MMR in a dominant manner. In vitro mismatch repair assay; kinetic DNA binding assays; ATPase activity measurement; excision step analysis with purified mutant proteins The Journal of biological chemistry High 22277660
2014 HDAC6 sequentially deacetylates and ubiquitinates MSH2, leading to its proteasomal degradation. HDAC6 reduces cellular MSH2 levels, decreases mismatch repair activity, and reduces cellular sensitivity to DNA-damaging agents. Co-immunoprecipitation; ubiquitination assay; HDAC6 depletion/overexpression; mismatch repair activity assay; cell sensitivity assay Molecular cell High 24882211
2014 Yeast Mlh1-Mlh3 is a metal-dependent endonuclease that is stimulated by Msh2-Msh3 to make single-strand breaks in supercoiled DNA, supporting a direct role for this endonuclease activity in resolving recombination intermediates and in mismatch repair. Purification of Mlh1-Mlh3; in vitro endonuclease assay; stimulation by purified Msh2-Msh3 The Journal of biological chemistry High 24403070
2014 PCNA and Msh2-Msh6 activate an Mlh1-Pms1 endonuclease pathway required for Exo1-independent mismatch repair. PCNA mutations disrupting Msh2-Msh6 binding or Mlh1-Pms1 endonuclease activation impair Exo1-independent MMR; Msh2-Msh6 localizes PCNA to repair sites after mispair recognition to activate the endonuclease. Genetic screen for PCNA mutants; mismatch repair assays; Mlh1-Pms1 focus accumulation assay; epistasis with msh6 PCNA-binding mutants Molecular cell High 24981171
2014 Depletion of MSH2 suppresses aberrant DNA damage response and ICL sensitivity in cells lacking FANCJ-MLH1 interaction, BRCA1, or FANCD2, demonstrating that MSH2-dependent DNA damage signaling underlies synthetic lethality in BRCA-FA pathway-deficient cells. Rescue is through a Rad18-dependent mechanism. siRNA depletion of MSH2; cell viability and ICL sensitivity assays; cell cycle analysis; Msh2 null mouse cells (Fancd2-null primary cells); epistasis with Rad18 The EMBO journal Medium 24966277
2016 MSH2-MSH3 acts as a component of the BER machinery to promote trinucleotide repeat expansion: MSH2-MSH3 stimulates DNA polymerase β (pol β) to copy through TNRs and enhances formation of the flap precursor for expansion, converting the outcome of TNR instability from deletion to expansion during oxidized base removal. In vitro BER reconstitution assay with purified MSH2-MSH3 and pol β; flap formation assay; deletion/expansion measurement with defined DNA substrates Nature communications High 27546332
2018 The C-terminal unstructured domain of yeast Exo1 contains two Msh2-interacting peptide (SHIP) boxes that interact with Msh2 to recruit Exo1 to repair sites. The msh2-M470I mutation eliminates SHIP-Msh2 interactions. Wild-type but not mutant SHIP peptides block Exo1-dependent MMR in vitro, establishing that Msh2 has a peptide-binding interface for Exo1 tethering. Yeast genetics; in vitro mismatch repair assay; SHIP peptide competition; mutagenesis (msh2-M470I); identification of new SHIP-box proteins Nature structural & molecular biology High 30061603
2013 MSH2 physically interacts with DNA polymerase kappa (Polκ). MSH2 depletion impairs PCNA monoubiquitination and the formation of UV-induced Polκ and other TLS polymerase foci. MSH2 can also regulate post-UV TLS polymerase focus formation in a PCNA monoubiquitination-independent fashion (in Rad18-deficient cells), facilitating translesion synthesis across CPD photoproducts. Co-immunoprecipitation combined with mass spectrometry; siRNA knockdown; focus formation assay after UV; TLS assay in living cells Nucleic acids research Medium 24038355
2021 OTUB1 (an OTU family deubiquitinase) inhibits MSH2 ubiquitination by blocking E2 ligase ubiquitin transfer activity. Depleting OTUB1 promotes ubiquitination and proteasomal degradation of MSH2, increases mutation frequency, and causes resistance to MNNG and cisplatin. Functional ubiquitination and deubiquitination assays; OTUB1 depletion in cells; mutation frequency assay; drug sensitivity assay The Journal of biological chemistry High 33640455
2003 MAX, the heterodimeric partner of c-MYC, physically interacts with MSH2 both in vitro (GST pull-down) and in vivo (co-immunoprecipitation from tumor cell extracts), identifying MAX as a binding partner of MSH2. Yeast two-hybrid; GST-fusion pull-down; co-immunoprecipitation from human tumor cell extracts Oncogene Medium 12584560
2022 MSH2 exerts a non-canonical epigenomic function in gastric cancer independent of its DNA repair catalytic activity: it binds tumor-associated super-enhancers controlling cell adhesion gene expression, enables chromatin rewiring and enhancer-promoter interactions, and maintains histone acetylation. This requires MSH6 and the SWI/SNF remodeler SMARCA4/BRG1. Loss of MSH2 causes deficient cell adhesion and synthetic lethality to BET inhibition. CRISPR-based mass spectrometry; genome-wide CRISPR functional screening; ChIP-seq; Hi-C (enhancer-promoter interaction); histone modification analysis; rescue experiments with catalytic-dead MSH2; in vitro and in vivo tumorigenesis assays Cancer research High 35583999
2006 Msh2 deficiency in primary mouse embryonic fibroblasts leads to chromosome aneuploidy, centrosome amplification, defective mitotic spindle organization, unequal chromosome segregation, and increased chromosome end-to-end fusions (telomere capping defects), without changes in telomerase activity, telomere length, or telomere recombination. Msh2(-/-) MEFs; cytogenetic analysis; centrosome immunofluorescence; telomere FISH; telomerase activity assay Oncogene Medium 16331258

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 2514 8252616
2011 Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 843 21642682
1996 Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair. Genes & development 503 8600025
2014 Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells. Cell 381 25036629
1995 MSH2 deficient mice are viable and susceptible to lymphoid tumours. Nature genetics 355 7550317
1994 MLH1, PMS1, and MSH2 interactions during the initiation of DNA mismatch repair in yeast. Science (New York, N.Y.) 292 8066446
1994 Structure of the human MSH2 locus and analysis of two Muir-Torre kindreds for msh2 mutations. Genomics 259 7713503
1990 A new homeobox-containing gene, msh-2, is transiently expressed early during mesoderm formation of Drosophila. Development (Cambridge, England) 222 1982429
2013 Cancer risks for MLH1 and MSH2 mutation carriers. Human mutation 196 23255516
2005 (CAG)(n)-hairpin DNA binds to Msh2-Msh3 and changes properties of mismatch recognition. Nature structural & molecular biology 189 16025128
2000 Functional interaction of proliferating cell nuclear antigen with MSH2-MSH6 and MSH2-MSH3 complexes. The Journal of biological chemistry 182 11005803
2004 An Msh2 point mutation uncouples DNA mismatch repair and apoptosis. Cancer research 155 14744764
1999 Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine. Proceedings of the National Academy of Sciences of the United States of America 152 10097137
2003 MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation. Proceedings of the National Academy of Sciences of the United States of America 144 14657349
2006 Prediction of MLH1 and MSH2 mutations in Lynch syndrome. JAMA 137 17003395
2017 MSH2 Loss in Primary Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 133 28790115
1997 Human MSH2 binds to trinucleotide repeat DNA structures associated with neurodegenerative diseases. Human molecular genetics 126 9215683
2014 HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα. Molecular cell 121 24882211
2013 Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities. Mutation research 117 23391514
2005 Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. International journal of cancer 113 15849733
2020 Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. American journal of human genetics 111 33357406
2014 Mlh1-Mlh3, a meiotic crossover and DNA mismatch repair factor, is a Msh2-Msh3-stimulated endonuclease. The Journal of biological chemistry 110 24403070
2000 Analysis of MLH1 and MSH2 expression in ovarian cancer before and after platinum drug-based chemotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research 103 10778972
2009 An Msh2 conditional knockout mouse for studying intestinal cancer and testing anticancer agents. Gastroenterology 93 19931261
2014 PCNA and Msh2-Msh6 activate an Mlh1-Pms1 endonuclease pathway required for Exo1-independent mismatch repair. Molecular cell 89 24981171
2003 Altered expression of MLH1, MSH2, and MSH6 in predisposition to hereditary nonpolyposis colorectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 85 14512394
2002 Transfer of the MSH2.MSH6 complex from proliferating cell nuclear antigen to mispaired bases in DNA. The Journal of biological chemistry 84 12435741
2009 MSH2 ATPase domain mutation affects CTG*CAG repeat instability in transgenic mice. PLoS genetics 80 19436705
2007 Saccharomyces cerevisiae Msh2-Msh3 acts in repair of base-base mispairs. Molecular and cellular biology 80 17636021
2003 Microsatellite instability and expression of MLH1 and MSH2 in carcinomas of the small intestine. Cancer 79 12627520
2002 Mutational specificity of mice defective in the MTH1 and/or the MSH2 genes. DNA repair 78 12531017
2005 Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. JAMA 76 15713769
1997 Enhancement of MSH2-MSH3-mediated mismatch recognition by the yeast MLH1-PMS1 complex. Current biology : CB 76 9368761
2005 Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants. Human genetics 75 16341550
2003 Identification and characterization of genomic rearrangements of MSH2 and MLH1 in Lynch syndrome (HNPCC) by novel techniques. Human mutation 75 12938096
2021 CircLIFR synergizes with MSH2 to attenuate chemoresistance via MutSα/ATM-p73 axis in bladder cancer. Molecular cancer 65 33874956
2002 Phosphorylation of mismatch repair proteins MSH2 and MSH6 affecting MutSalpha mismatch-binding activity. Nucleic acids research 62 11972333
1999 Removal of one nonhomologous DNA end during gene conversion by a RAD1- and MSH2-independent pathway. Genetics 61 10101166
2009 Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics. Human mutation 56 19267393
1998 Characterization of MLH1 and MSH2 alternative splicing and its relevance to molecular testing of colorectal cancer susceptibility. Human genetics 55 9490293
2002 Caenorhabditis elegans DNA mismatch repair gene msh-2 is required for microsatellite stability and maintenance of genome integrity. Proceedings of the National Academy of Sciences of the United States of America 54 11830642
2005 The role of MLH1, MSH2 and MSH6 in the development of multiple colorectal cancers. British journal of cancer 53 16106253
2004 Functional and physical interactions between ERCC1 and MSH2 complexes for resistance to cis-diamminedichloroplatinum(II) in mammalian cells. DNA repair 52 14706347
2002 Association of p53 and MSH2 with recombinative repair complexes during S phase. Oncogene 50 12101417
2014 Crosstalk between BRCA-Fanconi anemia and mismatch repair pathways prevents MSH2-dependent aberrant DNA damage responses. The EMBO journal 49 24966277
2016 Crosstalk between MSH2-MSH3 and polβ promotes trinucleotide repeat expansion during base excision repair. Nature communications 48 27546332
2009 Role of MUTYH and MSH2 in the control of oxidative DNA damage, genetic instability, and tumorigenesis. Cancer research 48 19435918
2010 Polymorphisms of MLH1 and MSH2 genes and the risk of lung cancer among never smokers. Lung cancer (Amsterdam, Netherlands) 46 21093954
1996 Mutation screening of MSH2 and MLH1 mRNA in hereditary non-polyposis colon cancer syndrome. Journal of medical genetics 46 8880570
2015 Relationship between MLH-1, MSH-2, PMS-2,MSH-6 expression and clinicopathological features in colorectal cancer. International journal of clinical and experimental pathology 44 26097592
2002 Mutation analysis of MLH1 and MSH2 genes performed by denaturing high-performance liquid chromatography. Journal of biochemical and biophysical methods 44 11879922
1998 Mismatch G-T binding activity and MSH2 expression is quantitatively related to sensitivity of cells to methylating agents. Carcinogenesis 44 9600339
2006 Saccharomyces cerevisiae MSH2-MSH3 and MSH2-MSH6 complexes display distinct requirements for DNA binding domain I in mismatch recognition. Journal of molecular biology 43 17157869
2011 Regulation of plant MSH2 and MSH6 genes in the UV-B-induced DNA damage response. Journal of experimental botany 42 21307385
2011 Mutation deep within an intron of MSH2 causes Lynch syndrome. Familial cancer 42 21360204
2018 Identification of Exo1-Msh2 interaction motifs in DNA mismatch repair and new Msh2-binding partners. Nature structural & molecular biology 41 30061603
2006 Msh2 deficiency leads to chromosomal abnormalities, centrosome amplification, and telomere capping defect. Oncogene 41 16331258
2003 p53, mdm2, EGFR, and msh2 expression in paired initial and recurrent glioblastoma multiforme. Journal of neurology, neurosurgery, and psychiatry 40 12754350
2003 Alterations in PMS2, MSH2 and MLH1 expression in human prostate cancer. International journal of oncology 38 12684669
2004 Germline truncating mutations in both MSH2 and BRCA2 in a single kindred. British journal of cancer 36 14735197
2001 1,2-Dimethylhydrazine-induced colon carcinoma and lymphoma in msh2(-/-) mice. Journal of the National Cancer Institute 36 11604476
2002 DNA binding properties of the yeast Msh2-Msh6 and Mlh1-Pms1 heterodimers. Biological chemistry 34 12222686
2007 Conditional expression of mutated K-ras accelerates intestinal tumorigenesis in Msh2-deficient mice. Oncogene 33 17297472
2009 MSH2 deficiency abolishes the anticancer and pro-aging activity of short telomeres. Aging cell 32 18986375
2014 Promoter methylation of MLH1, PMS2, MSH2 and p16 is a phenomenon of advanced-stage HCCs. PloS one 31 24400091
2009 The nucleotide binding dynamics of human MSH2-MSH3 are lesion dependent. Nature structural & molecular biology 31 19377479
2008 Origins and prevalence of the American Founder Mutation of MSH2. Cancer research 31 18381419
2013 Promoter hypermethylation of DNA repair genes MLH1 and MSH2 in adenocarcinomas and squamous cell carcinomas of the lung. Revista portuguesa de pneumologia 30 24360395
2012 Biochemical analysis of the human mismatch repair proteins hMutSα MSH2(G674A)-MSH6 and MSH2-MSH6(T1219D). The Journal of biological chemistry 30 22277660
2018 MSH2 Gene Point Mutations Are Not Antifungal Resistance Markers in Candida glabrata. Antimicrobial agents and chemotherapy 29 30397068
2007 The phenotypic expression of three MSH2 mutations in large Newfoundland families with Lynch syndrome. Familial cancer 29 17039271
2003 Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX. Oncogene 29 12584560
2021 OTUB1 stabilizes mismatch repair protein MSH2 by blocking ubiquitination. The Journal of biological chemistry 28 33640455
2017 BRCA2, EGFR, and NTRK mutations in mismatch repair-deficient colorectal cancers with MSH2 or MLH1 mutations. Oncotarget 28 28591715
2018 Reduced Expression of Mismatch Repair Genes MSH6/MSH2 Directly Promotes Pituitary Tumor Growth via the ATR-Chk1 Pathway. The Journal of clinical endocrinology and metabolism 27 29342268
2013 Mismatch repair protein MSH2 regulates translesion DNA synthesis following exposure of cells to UV radiation. Nucleic acids research 27 24038355
2014 Mesalazine and thymoquinone attenuate intestinal tumour development in Msh2(loxP/loxP) Villin-Cre mice. Gut 26 25429050
2011 Expression analysis of TOP2A, MSH2 and MLH1 genes in MCF7 cells at different levels of etoposide resistance. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 25 22285073
2010 Epigenetic inactivation of HOXA5 and MSH2 gene in clear cell renal cell carcinoma. Pathology international 24 20846263
2005 Opposing roles for DNA structure-specific proteins Rad1, Msh2, Msh3, and Sgs1 in yeast gene targeting. The EMBO journal 24 15920474
1994 Cloning and expression of the Xenopus and mouse Msh2 DNA mismatch repair genes. Nucleic acids research 24 7838728
2018 Expressional analysis of MLH1 and MSH2 in breast cancer. Current problems in cancer 23 30149959
2014 Expression of DNA mismatch repair proteins MLH1, MSH2, and MSH6 in recurrent glioblastoma. Neurological research 22 24995467
2012 Cisplatin upregulates MSH2 expression by reducing miR-21 to inhibit A549 cell growth. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 22 23485110
1994 Hereditary nonpolyposis colon cancer: analysis of linkage to 2p15-16 places the COCA1 locus telomeric to D2S123 and reveals genetic heterogeneity in seven Canadian families. American journal of human genetics 22 8198129
2023 MSH2 stimulates interfering and inhibits non-interfering crossovers in response to genetic polymorphism. Nature communications 21 37872134
2019 Clinical significance of MLH1/MSH2 for stage II/III sporadic colorectal cancer. World journal of gastrointestinal oncology 21 31798786
2003 Age-related expression of p53, Mdm2, EGFR and Msh2 in glioblastoma multiforme. Zentralblatt fur Neurochirurgie 21 12582944
2009 Conformational change in MSH2-MSH6 upon binding DNA coupled to ATPase activity. Biophysical journal 20 19486659
2005 MSH2 missense mutations alter cisplatin cytotoxicity and promote cisplatin-induced genome instability. Nucleic acids research 20 15947132
2001 Msh-2 suppresses in vivo mutation in a gene dose and lesion dependent manner. Oncogene 20 11429706
2019 Elucidating the role of interacting residues of the MSH2-MSH6 complex in DNA repair mechanism: A computational approach. Advances in protein chemistry and structural biology 19 30798936
2008 MSH2 missense mutations and HNPCC syndrome: pathogenicity assessment in a human expression system. Human mutation 19 18781619
2020 Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma. Frontiers in oncology 18 32154170
2007 The effects of MSH2 deficiency on spontaneous and radiation-induced mutation rates in the mouse germline. Mutation research 18 17331550
2014 Expression of MSH2 and MSH6 on a tissue microarray in patients with osteosarcoma. Anticancer research 17 25503122
2017 Loss of MSH2 and MSH6 due to heterozygous germline defects in MSH3 and MSH6. Familial cancer 16 28528517
2002 Msh2 deficiency increases the mutation frequency in all parts of the mouse colon. Environmental and molecular mutagenesis 15 12489114
2022 Chromatin Rewiring by Mismatch Repair Protein MSH2 Alters Cell Adhesion Pathways and Sensitivity to BET Inhibition in Gastric Cancer. Cancer research 14 35583999
2003 Msh2 deficiency enhances somatic Apc and p53 mutations in Apc+/-Msh2-/- mice. Carcinogenesis 14 12584170

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