Affinage

MSH3

DNA mismatch repair protein Msh3 · UniProt P20585

Length
1137 aa
Mass
127.4 kDa
Annotated
2026-06-10
100 papers in source corpus 34 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

MSH3 is the DNA-mismatch-recognizing subunit of the MutSβ heterodimer (MSH2-MSH3), which binds insertion/deletion loops and branched DNA structures and directs their repair, defining a substrate specificity distinct from the MSH2-MSH6 (MutSα) heterodimer that handles base-base mispairs (PMID:8805366, PMID:8600025, PMID:8631743, PMID:9671718). Mismatch recognition is concentrated in the MSH3 mispair-binding domain, which dictates loop-binding specificity and uses distinct DNA contacts for small versus large insertion/deletion substrates (PMID:17573527, PMID:20421420), while a domain-I deletion in the MSH2 partner selectively abolishes all MutSβ functions (PMID:17157869). Productive repair requires more than DNA binding: upon loop engagement, ATP binding and hydrolysis within the MSH3 subunit drive ADP-ATP exchange in MSH2, converting the complex into a sliding clamp that recruits MutL partners (MLH1-PMS1 or MLH1-MLH3), and MSH2-MSH3 stimulates the metal-dependent MLH1-MLH3 endonuclease (PMID:19377479, PMID:24550389, PMID:24403070). MSH3 anchors its function to the replication fork through an N-terminal PCNA-binding motif (PMID:11005803). Beyond canonical mismatch repair, MutSβ recognizes 3' branched/junction intermediates in double-strand break repair, where it directly recruits the Rad1-Rad10 endonuclease via Saw1, is itself recruited to breaks through SMARCAD1, and promotes EXO1-driven long-range resection and homologous recombination while antagonizing polymerase theta-mediated end-joining (PMID:9256462, PMID:29660012, PMID:37140056). Paradoxically, MutSβ drives trinucleotide repeat expansion: it becomes conformationally trapped on CAG-hairpin DNA, which inhibits its own ATPase, and it interferes with Okazaki-fragment processing and base-excision repair to bias the outcome toward expansion — a process requiring MutSβ abundance, MSH3 ATPase activity, and MutL interactions rather than DNA binding alone (PMID:16025128, PMID:21960445, PMID:22938864, PMID:28973443, PMID:39790027). MSH3 protein abundance is controlled by SYVN1-mediated ubiquitination and proteasomal/lysosomal degradation, and its nuclear localization is governed by NLS/NES signals, with IL-6-induced nuclear export linking inflammatory signaling to its genome-stabilizing activity (PMID:32284349, PMID:35334159).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 High

    Establishing that MSH3 forms a defined heterodimer with MSH2 with its own substrate preference answered whether MSH3 is a functional MMR component distinct from MSH6.

    Evidence Purified MSH2-MSH3 heterodimer in EMSA with defined mismatch substrates, plus genetic epistasis and in vitro repair in yeast and human cells

    PMID:8600025 PMID:8631743 PMID:8782829 PMID:8805366

    Open questions at the time
    • Structural basis of loop versus base-base discrimination not yet defined
    • Did not resolve the ATPase/conformational mechanism of repair signaling
  2. 1996 High

    Placing MSH2-MSH3 in the RAD1-RAD10 recombination pathway revealed a function beyond mismatch repair in removing non-homologous DNA ends.

    Evidence Genetic epistasis with null mutants and recombination/gene-conversion assays in S. cerevisiae

    PMID:8849883 PMID:9256462

    Open questions at the time
    • Did not establish direct physical recruitment of the Rad1-Rad10 endonuclease
  3. 1997 High

    Showing MutL homolog stimulation of MutSβ binding addressed how mismatch recognition is coupled to downstream repair machinery.

    Evidence Purified yeast MLH1-PMS1 with EMSA stimulation of MSH2-MSH3 binding, plus heterodimer-balance experiments in amplified cells

    PMID:9294177 PMID:9368761 PMID:9671718

    Open questions at the time
    • Did not define the order of conformational and nucleotide events linking MutSβ and MutL
  4. 1998 High

    Identifying MLH3 as an alternate MutL partner clarified which downstream complex acts specifically in the MSH3-dependent branch.

    Evidence Genetic epistasis with frameshift reporters and yeast two-hybrid in S. cerevisiae

    PMID:9770499

    Open questions at the time
    • Did not establish enzymatic output of MLH1-MLH3 at this stage
  5. 2000 High

    Demonstrating an MSH3 PCNA-binding motif explained how MutSβ is coupled to the replication fork during repair.

    Evidence Peptide-PCNA binding, alanine-substitution mutagenesis with in vivo mutation rate and in vitro repair readouts

    PMID:11005803

    Open questions at the time
    • Structural detail of the MSH3-PCNA interface not resolved
    • Relative contribution to loading versus processivity unclear
  6. 2002 High

    Linking Msh3 to somatic CAG/CTG expansion in vivo reframed MutSβ as a driver, not just repairer, of repeat instability.

    Evidence Msh3-/- and Msh6-/- crosses into DM1 knock-in mice with tissue-specific repeat-size analysis

    PMID:11809728

    Open questions at the time
    • Did not define the molecular mechanism by which Msh3 promotes rather than corrects expansion
  7. 2011 High

    Characterizing MutSβ trapping on CAG hairpins provided the molecular mechanism by which a repair factor becomes pro-mutagenic.

    Evidence Purified-protein ATPase, nucleotide-binding, EMSA, SAXS and single-molecule FRET on CAG-hairpin and loop substrates

    PMID:16025128 PMID:21960445

    Open questions at the time
    • Did not show how trapping is resolved or processed in the cell
    • In vivo relevance of the trapped conformation not directly demonstrated
  8. 2009 High

    Defining the asymmetric nucleotide cycle of MutSβ established how ATP hydrolysis in MSH3 powers sliding-clamp formation distinct from MutSα.

    Evidence Purified human MSH2-MSH3 nucleotide binding/exchange and ATPase assays with defined loop substrates

    PMID:19377479

    Open questions at the time
    • Did not connect the nucleotide cycle to a structural conformational state
  9. 2014 High

    Reconstituting sliding-clamp formation, MutL recruitment, and MLH1-MLH3 endonuclease stimulation completed the biochemical chain from recognition to incision.

    Evidence Purified yeast proteins, EMSA sliding-clamp and Mlh1-Pms1 recruitment assays, MLH1-MLH3 endonuclease assays, separation-of-function FLY-motif mutants

    PMID:23458407 PMID:24403070 PMID:24550389 PMID:24746922

    Open questions at the time
    • How distinct ATP requirements partition MMR versus NHTR functions not fully resolved
  10. 2012 High

    Showing MutSβ interferes with Okazaki-fragment processing and biases base-excision repair gave replication- and BER-linked mechanisms for incremental expansion.

    Evidence In vivo yeast TNR expansion assays plus in vitro reconstituted Okazaki-fragment and BER assays with purified FEN1, ligase, pol β

    PMID:22938864 PMID:27546332

    Open questions at the time
    • Relative in vivo contributions of replication versus BER routes not quantified
  11. 2017 High

    Demonstrating that abundance and ATPase activity (not just DNA binding) gate expansion clarified which MutSβ activities are rate-limiting.

    Evidence Msh3-null cells with variant add-back, ATPase-defective mutagenesis, repeat expansion assays in isogenic lines

    PMID:28973443

    Open questions at the time
    • Did not isolate the specific downstream MutL-dependent step required
  12. 2018 High

    Identifying direct Rad1-Rad10 recruitment through Msh2-Msh3 and Saw1 established the physical basis of the DSB end-removal role.

    Evidence Separation-of-function rad1 alleles, reciprocal Co-IP, and ChIP of repair intermediates in yeast

    PMID:29660012

    Open questions at the time
    • Stoichiometry and architecture of the Msh2-Msh3-Saw1-Rad1-Rad10 assembly unknown
  13. 2020 High

    Mapping MSH3 NLS/NES signals and IL-6-induced export connected inflammatory signaling to MSH3 nuclear availability.

    Evidence Systematic NLS/NES mutagenesis and localization imaging under IL-6 stimulation in human cells

    PMID:32284349

    Open questions at the time
    • Export receptor and signaling intermediates not identified
    • Functional consequence on repair quantified only indirectly
  14. 2022 Medium

    Identifying SYVN1-mediated ubiquitination established how MSH3 protein abundance is post-translationally controlled.

    Evidence Co-IP, ubiquitination and half-life assays with proteasome/lysosome inhibitors and UVB treatment in lens epithelial cells

    PMID:35334159

    Open questions at the time
    • Single lab; ubiquitination sites on MSH3 not mapped
    • Generality beyond lens epithelial cells not established
  15. 2023 Medium

    Linking MutSβ to SMARCAD1, EXO1, and POLθ antagonism defined its role in resection-based pathway choice during DSB repair.

    Evidence Co-IP, DSB-site recruitment ChIP, EXO1 activity assay, and HR/TMEJ reporter assays

    PMID:37140056

    Open questions at the time
    • Single lab; reciprocal validation of interactions limited
    • Whether this is conserved with yeast NHTR role unclear
  16. 2025 Medium

    Showing that the MSH3 MBD alone cannot drive expansion separated DNA-binding from the coordinated ATPase/MutL activities required for the pro-mutagenic outcome.

    Evidence Msh3 MBD-swap chimera into Msh6 with in vivo TNR expansion assay in S. cerevisiae

    PMID:39790027

    Open questions at the time
    • Single lab; chimera may not fully recapitulate native MutSβ context
    • Specific MutL-dependent step still unidentified

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how MSH3 abundance, nuclear localization, and conformational trapping are integrated in human disease tissues to determine whether MutSβ stabilizes the genome or drives repeat expansion.
  • No structural model of human MutSβ trapped on hairpin DNA in the corpus
  • Tissue-specific regulation of MSH3 levels in expansion-prone neurons not characterized
  • Mechanistic link between SYVN1/IL-6 regulation and repeat instability untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 6 GO:0140657 ATP-dependent activity 5 GO:0140097 catalytic activity, acting on DNA 3 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2
Pathway
R-HSA-73894 DNA Repair 5 R-HSA-1643685 Disease 3
Partners
EXO1MLH1MLH3MSH2PCNAPMS1SMARCAD1SYVN1
Complex memberships
MutSβ (MSH2-MSH3)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 MSH2 and MSH3 form a stable heterodimer (MutSβ) that binds insertion/deletion mismatches with high specificity but has low affinity for G/T base-base mismatches, establishing distinct mispair-recognition specificities between MSH2-MSH3 and MSH2-MSH6. Protein purification to near homogeneity, electrophoretic mobility shift assay (EMSA) with defined mismatch substrates Current biology : CB High 8805366
1996 In S. cerevisiae, MSH3 and MSH6 constitute alternate, partially redundant pathways of MSH2-dependent mismatch repair: MSH2-MSH6 repairs base-base and small insertion/deletion mispairs, while MSH2-MSH3 specifically repairs insertion/deletion mispairs. Loss of both MSH3 and MSH6 phenocopies msh2 null mutants. Genetic epistasis analysis using single and double null mutants, mutation rate assays, microsatellite instability measurement Genes & development High 8600025 8631743
1996 MSH3 functions in mitotic recombination in the RAD1-RAD10 pathway in S. cerevisiae; epistasis analysis placed MSH2 and MSH3 in the same recombination pathway as RAD1 and RAD10 for removal of non-homologous ends. Genetic epistasis analysis with null mutants, recombination rate measurement, homologous integration assays Genetics High 8849883 9256462
1996 MSH3 frameshift mutation in an endometrial carcinoma cell line causes deficient repair of DNA substrates containing mismatches or extra nucleotides; introduction of chromosome 5 (encoding MSH3) partially restored repair of some insertion/deletion substrates but not all, consistent with MSH3 having substrate-specific repair activity. Cell line mutation analysis, in vitro mismatch repair assay with cell extracts, microcell-mediated chromosome transfer Nature genetics High 8782829
1997 In S. cerevisiae DSB repair, Msh2 and Msh3 (but not Msh6, Pms1, or Mlh1) are required for removal of non-homologous DNA ends before new DNA synthesis in gene conversion and single-strand annealing pathways; Msh2/Msh3 recognize branched DNA structures with a free 3' tail. Genetic analysis of recombination using DSB-induced gene conversion and single-strand annealing assays in mismatch repair gene deletion strains Proceedings of the National Academy of Sciences of the United States of America High 9256462
1997 The yeast MLH1-PMS1 heterodimer enhances mismatch binding by the MSH2-MSH3 heterodimer; MLH1-PMS1 alone shows no affinity for mismatched DNA, but greatly stimulates MSH2-MSH3 mismatch recognition. Purification of yeast MLH1-PMS1 heterodimer to near homogeneity, EMSA/gel shift assay Current biology : CB High 9368761
1997 Overexpression of MSH3 due to DHFR/MSH3 gene amplification in methotrexate-resistant HL-60R cells causes MSH2 to be sequestered predominantly into MutSβ (MSH2-MSH3), depleting MutSα (MSH2-MSH6) and causing degradation of partnerless MSH6, leading to deficient base-base mismatch repair while preserving loop repair. Rapid purification of MutSα and MutSβ from cell extracts, quantification of heterodimer ratios, in vitro mismatch repair complementation assay Proceedings of the National Academy of Sciences of the United States of America High 9294177 9671718
1998 Recombinant hMutSβ (hMSH2/hMSH3) repairs insertion-deletion loops but not base-base mispairs in vitro, whereas hMutSα (hMSH2/hMSH6) repairs both; demonstrating distinct substrate specificities of the two human heterodimers. Recombinant protein preparation, in vitro mismatch repair complementation assay in HEC59 cell extracts Proceedings of the National Academy of Sciences of the United States of America High 9671718
1998 MLH3 functions in the MSH3-dependent mismatch repair pathway in S. cerevisiae: mlh3 and msh3 mutations are epistatic (double mutant is not additive), and MLH3 interacts with MLH1 in a two-hybrid system, suggesting a heterodimeric MLH1-MLH3 complex acts in place of MLH1-PMS1 for repair of specific insertion/deletion mispairs. Genetic epistasis using frameshift reporter assays (hom3-10 reversion, LYS2 frameshift hotspots), yeast two-hybrid interaction Proceedings of the National Academy of Sciences of the United States of America High 9770499
2000 MSH3 (and MSH6), but not MSH2, contain N-terminal PCNA-binding motif sequences; peptides and intact complexes bind PCNA, and alanine substitutions in the PCNA-binding motif of Msh3 elevate mutation rates in yeast, demonstrating that MSH3-PCNA interaction is important for MMR function. Peptide-PCNA binding assays, site-directed mutagenesis of PCNA-binding motif, in vivo mutation rate assay, mismatch repair inhibition assay in human cell extracts The Journal of biological chemistry High 11005803
2002 In Msh3-deficient DM1 knock-in mice, somatic (CTG)n repeat expansion is completely blocked, whereas Msh6 deficiency increases the frequency of somatic expansions; competition of Msh3 and Msh6 for binding to Msh2 in complexes with different DNA recognition specificities explains differential effects on somatic repeat instability. Mouse knockout genetics (Msh3-/- and Msh6-/- backgrounds crossed to DM1 knock-in mice), somatic repeat size analysis across tissues Human molecular genetics High 11809728
2005 Purified MSH2-MSH3 binds CAG-hairpin DNA (an expansion intermediate); CAG-hairpin binding inhibits the ATPase activity of MSH2-MSH3 and alters nucleotide (ADP and ATP) affinity and protein-DNA binding interfaces in a manner dependent on A·A mispaired bases in the stem and the hairpin structure, identifying functional defects that could misdirect repair toward expansion. Purified protein biochemistry, ATPase assay, DNA binding assays with synthetic substrates, nucleotide binding measurements Nature structural & molecular biology High 16025128
2006 Purified S. cerevisiae MSH2-MSH3 specifically binds branched DNA substrates containing 3' single-stranded DNA at the double-strand/single-strand junction; ATP stimulates its release; chemical footprinting shows MSH2-MSH3 binding opens the junction, creating a nucleoprotein structure predicted to signal downstream repair. EMSA, chemical footprinting analysis, ATP-modulated binding assays with defined branched DNA substrates Journal of molecular biology High 16781730
2006 The mismatch-binding domain (MBD) of MSH3, when swapped into MSH6, confers MSH3-like mispair-binding specificity while retaining MSH6-like genetic interaction properties with MutL homologs; communication between the MBD and ATPase domain is conserved between Msh2-Msh3 and Msh2-Msh6. Chimeric protein construction, in vivo genetic mismatch repair assays, biochemical mismatch binding specificity analysis Proceedings of the National Academy of Sciences of the United States of America High 17573527
2006 In S. cerevisiae, deletion of the conserved mismatch recognition domain I (Delta1) of MSH2 causes a separation-of-function: MSH2-MSH3-mediated MMR and recombination functions are completely abolished, while MSH2-MSH6-mediated MMR is nearly wild-type; domain I of MSH3 contributes to mispair binding specificity and suppresses non-specific DNA binding. Domain deletion mutagenesis, in vivo mutation rate assays, in vitro mismatch binding specificity assays with purified proteins Journal of molecular biology High 17157869
2007 S. cerevisiae Msh2-Msh3 recognizes and repairs specific base-base mispairs (particularly GC→CG and AT→TA transversions) in addition to insertion/deletion mispairs, as shown by altered mutation spectrum in msh3 mutants and direct biochemical binding of Msh2-Msh3 to specific base-base mispair substrates. CAN1 forward mutation assay for mutation spectrum, purified Msh2-Msh3 binding assays with substrates derived from in vivo mutation spectrum Molecular and cellular biology High 17636021
2009 Human MSH2-MSH3 recognizes small loops via a distinct nucleotide-binding mechanism from MSH2-MSH6: upon DNA loop binding, MSH2-MSH3 adopts a specific nucleotide signature (MSH2 subunit bound to ADP, MSH3 subunit empty); subsequent ATP binding and hydrolysis in the MSH3 subunit drives ADP-ATP exchange in MSH2, requiring ATP hydrolysis (not just ATP stabilization) for ADP release. Purified human MSH2-MSH3, nucleotide binding and exchange assays, ATPase assays with defined DNA substrates Nature structural & molecular biology High 19377479
2010 Homology modeling of the Msh3 mispair-binding domain and point mutagenesis identified two functional classes: mutations disrupting repair of both small and large insertion/deletion mispairs (also defective in non-homologous tail removal in DSB repair), and mutations selectively disrupting small insertion/deletion repair only; indicating Msh3 uses distinct DNA contacts for small vs. large insertion/deletion recognition. Homology modeling, site-directed mutagenesis, in vivo MMR assays, in vivo DSB repair assay Molecular and cellular biology Medium 20421420
2011 MSH2-MSH3 is conformationally trapped on repair-resistant CAG loop DNA: MSH2/MSH3 binds, bends, and dissociates from repair-competent loops but cannot dissociate from CAG loops, which adopt a unique DNA junction conformation; this trapping inhibits downstream repair signaling. EMSA, SAXS, single-molecule FRET, gel-based DNA binding/bending assays with repair-competent vs. CAG loop substrates Proceedings of the National Academy of Sciences of the United States of America High 21960445
2012 Msh2-Msh3 promotes CTG and CAG repeat expansions in S. cerevisiae in vivo and directly interferes with Okazaki fragment processing by blocking flap endonuclease 1 (Rad27/FEN1) and DNA ligase I (Cdc9) activities on TNR-containing substrates in vitro, providing a mechanism for incremental expansion during lagging-strand replication. In vivo TNR expansion assay in yeast, in vitro reconstituted Okazaki fragment processing assay with purified proteins Cell reports High 22938864
2013 MSH3 deficiency sensitizes colorectal cancer cells to cisplatin and oxaliplatin independently of the canonical MMR pathway (MLH1-independent), and MSH3-deficient cells accumulate higher levels of γH2AX and 53BP1 after platinum treatment, demonstrating that MSH3 plays a role in repairing DNA double-strand breaks induced by platinum drugs. shRNA knockdown in isogenic HCT116 clones, clonogenic survival assay, γH2AX and 53BP1 foci immunofluorescence, MLH1 siRNA epistasis The Journal of biological chemistry Medium 21285347
2014 Purified S. cerevisiae Msh2-Msh3 forms sliding clamps and recruits Mlh1-Pms1 specifically on +1 to +4 insertion/deletions and CC, AA, and possibly GG mispairs; the nucleotide binding domain and communicating regions (not the mispair-binding domain) are responsible for the rapid dissociation of Msh2-Msh3 sliding clamps compared to Msh2-Msh6. Purified proteins, EMSA sliding clamp assay, Mlh1-Pms1 recruitment assay, chimeric Msh2-Msh6/Msh3 protein analysis The Journal of biological chemistry High 24550389
2014 Mlh1-Mlh3 is a metal-dependent endonuclease whose activity is stimulated by Msh2-Msh3; this stimulation supports a direct role for the Msh2-Msh3/Mlh1-Mlh3 axis in resolving meiotic recombination intermediates and in DNA mismatch repair. Protein purification, endonuclease activity assay (cleavage of supercoiled DNA), metal dependence analysis The Journal of biological chemistry High 24403070
2014 Aromatic residues in the FLY motif of the Msh3 nucleotide binding pocket are essential for MMR but largely dispensable for 3' non-homologous tail removal (3' NHTR) in DSB repair; substrate-dependent differences in ATP hydrolysis and nucleotide turnover by Msh2-Msh3 indicate the two repair pathways have distinct requirements for ATP positioning within Msh3. In vivo MMR and 3' NHTR assays in yeast, purified Msh2-msh3Y942A ATPase and DNA binding assays, separation-of-function mutagenesis DNA repair High 23458407 24746922
2016 MSH2-MSH3 crosstalk with base excision repair promotes trinucleotide repeat expansion: MSH2-MSH3 stimulates pol β to copy through TNR sequences and enhances formation of the flap expansion precursor during BER, shifting the outcome from deletion to expansion. In vitro reconstituted BER assay with purified proteins (pol β, MSH2-MSH3, FEN1, ligase), TNR substrate analysis Nature communications High 27546332
2017 MutSβ (Msh2-Msh3) abundance drives CTG•CAG repeat expansions: Msh3 overexpression elevates MutSβ levels and expansion activity; an ATPase-defective Msh3 mutant completely abolishes expansions at normal expression levels; two polymorphic Msh3 variants primarily affect protein stability rather than activity. Msh3-null cells with add-back of Msh3 variants, repeat expansion assay in isogenic cell lines, ATPase-defective Msh3 mutagenesis Nucleic acids research High 28973443
2018 Rad1-Rad10 is recruited and positioned at recombination intermediates through specific interactions with Msh2-Msh3 and Saw1; rad1 separation-of-function alleles that disrupt Msh2-Msh3 and Saw1 interactions abolish 3' NHTR but are functional for NER, establishing Msh2-Msh3 as a direct recruiter of the Rad1-Rad10 endonuclease complex in DSB repair. Genetic separation-of-function alleles, co-immunoprecipitation, chromatin immunoprecipitation of repair intermediates, in vitro interaction assays Nucleic acids research High 29660012
2020 MSH3 contains functional nuclear localization signals (NLS1 and NLS2, with NLS1 dominant) and two nuclear export signals (NES1 and NES2) that work synergistically; IL-6 stimulation triggers MSH3 nuclear export dependent on both NES1 and NES2; a 27-bp deletion in exon 1 (Δ27bp) adjacent to NLS1 compromises nuclear import under oxidative stress. Site-directed mutagenesis of NLS and NES sequences in full-length MSH3, live-cell imaging/immunofluorescence of localization, IL-6 stimulation assay Molecular and cellular biology High 32284349
2022 E3 ubiquitin ligase SYVN1 (synoviolin) interacts with MSH3, promotes its ubiquitination and degradation via both the ubiquitin-proteasome pathway and the autophagy-lysosome pathway; UVB irradiation accelerates MSH3 degradation through this mechanism; ectopic MSH3 expression impedes UVB-induced apoptosis in lens epithelial cells. Co-immunoprecipitation, protein half-life assay, shRNA knockdown, ubiquitination assay, proteasome and lysosome inhibitor experiments The FEBS journal Medium 35334159
2023 MSH2-MSH3 is recruited to DNA double-strand break sites through interaction with the chromatin remodeling protein SMARCAD1; once recruited, MSH2-MSH3 facilitates EXO1 recruitment and enhances EXO1 enzymatic activity for long-range DNA end resection; MSH2-MSH3 also inhibits POLθ access, thereby promoting homologous recombination over polymerase theta-mediated end-joining (TMEJ). Co-immunoprecipitation, DSB site recruitment assays (ChIP), EXO1 activity assay, TMEJ reporter assay, HR reporter assay Nucleic acids research Medium 37140056
2011 Mouse MSH3 is a nucleoplasmic protein with finely granular distribution largely absent from condensed heterochromatin; under stress conditions (ethanol or hydrogen peroxide), MSH3 redistributes into nuclear bodies containing PCNA. Monoclonal antibody generation in Msh3-knockout mice, immunofluorescence in cultured mouse cells, specificity confirmed by absence of staining in Msh3-knockout cells Journal of cellular biochemistry Medium 21344488
2025 Msh2-Msh3 DNA-binding activity alone (via its mispair-binding domain) is not sufficient to promote trinucleotide repeat expansions; a chimeric Msh complex with the Msh3 MBD replacing Msh6's MBD retained Msh3-like DNA binding but did not promote TNR expansions, demonstrating that TNR expansion requires coordinated ATP binding, hydrolysis, and MutL complex interactions beyond DNA binding alone. Chimeric Msh2-Msh3/Msh6 protein with domain swap, in vivo TNR expansion assay in S. cerevisiae Genetics Medium 39790027

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair. Genes & development 503 8600025
1997 Role of Saccharomyces cerevisiae Msh2 and Msh3 repair proteins in double-strand break-induced recombination. Proceedings of the National Academy of Sciences of the United States of America 269 9256462
2002 Somatic expansion behaviour of the (CTG)n repeat in myotonic dystrophy knock-in mice is differentially affected by Msh3 and Msh6 mismatch-repair proteins. Human molecular genetics 239 11809728
1998 The Saccharomyces cerevisiae MLH3 gene functions in MSH3-dependent suppression of frameshift mutations. Proceedings of the National Academy of Sciences of the United States of America 237 9770499
2005 (CAG)(n)-hairpin DNA binds to Msh2-Msh3 and changes properties of mismatch recognition. Nature structural & molecular biology 189 16025128
2016 Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. American journal of human genetics 187 27476653
2000 Functional interaction of proliferating cell nuclear antigen with MSH2-MSH6 and MSH2-MSH3 complexes. The Journal of biological chemistry 182 11005803
1999 HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions. Nature genetics 180 10545954
1998 Mismatch repair deficiency associated with overexpression of the MSH3 gene. Proceedings of the National Academy of Sciences of the United States of America 177 9671718
1996 Requirement of the yeast MSH3 and MSH6 genes for MSH2-dependent genomic stability. The Journal of biological chemistry 170 8631743
1996 Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair. Nature genetics 164 8782829
2000 Somatic hypermutation in MutS homologue (MSH)3-, MSH6-, and MSH3/MSH6-deficient mice reveals a role for the MSH2-MSH6 heterodimer in modulating the base substitution pattern. The Journal of experimental medicine 155 10662804
1993 The yeast gene MSH3 defines a new class of eukaryotic MutS homologues. Molecular & general genetics : MGG 142 8510668
1997 DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutSalpha/hMutSbeta ratio and reduces the efficiency of base-base mismatch repair. Proceedings of the National Academy of Sciences of the United States of America 138 9294177
1996 Binding of insertion/deletion DNA mismatches by the heterodimer of yeast mismatch repair proteins MSH2 and MSH3. Current biology : CB 138 8805366
2013 MSH3 polymorphisms and protein levels affect CAG repeat instability in Huntington's disease mice. PLoS genetics 136 23468640
1995 Mutations in the MSH3 gene preferentially lead to deletions within tracts of simple repetitive DNA in Saccharomyces cerevisiae. Proceedings of the National Academy of Sciences of the United States of America 134 7479796
2000 The DNA mismatch repair genes Msh3 and Msh6 cooperate in intestinal tumor suppression. Cancer research 133 10706084
2019 MSH3 modifies somatic instability and disease severity in Huntington's and myotonic dystrophy type 1. Brain : a journal of neurology 131 31216018
2004 A role for Msh6 but not Msh3 in somatic hypermutation and class switch recombination. The Journal of experimental medicine 126 15238605
1998 Functional overlap in mismatch repair by human MSH3 and MSH6. Genetics 126 9560383
1996 Requirement of mismatch repair genes MSH2 and MSH3 in the RAD1-RAD10 pathway of mitotic recombination in Saccharomyces cerevisiae. Genetics 114 8849883
2014 Mlh1-Mlh3, a meiotic crossover and DNA mismatch repair factor, is a Msh2-Msh3-stimulated endonuclease. The Journal of biological chemistry 110 24403070
2007 Saccharomyces cerevisiae Msh2-Msh3 acts in repair of base-base mispairs. Molecular and cellular biology 80 17636021
2006 Mismatch repair factor MSH2-MSH3 binds and alters the conformation of branched DNA structures predicted to form during genetic recombination. Journal of molecular biology 76 16781730
1997 Enhancement of MSH2-MSH3-mediated mismatch recognition by the yeast MLH1-PMS1 complex. Current biology : CB 76 9368761
2011 MSH3 mediates sensitization of colorectal cancer cells to cisplatin, oxaliplatin, and a poly(ADP-ribose) polymerase inhibitor. The Journal of biological chemistry 74 21285347
2016 A polymorphism in the MSH3 mismatch repair gene is associated with the levels of somatic instability of the expanded CTG repeat in the blood DNA of myotonic dystrophy type 1 patients. DNA repair 72 26994442
2010 Association between genetic polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT genes and radiosensitivity in breast cancer patients. International journal of radiation oncology, biology, physics 68 20708344
2006 Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6. Carcinogenesis 64 16728433
2014 A functional cancer genomics screen identifies a druggable synthetic lethal interaction between MSH3 and PRKDC. Cancer discovery 61 24556366
2001 MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer. Cancer research 61 11245474
2001 The distinct spectra of tumor-associated Apc mutations in mismatch repair-deficient Apc1638N mice define the roles of MSH3 and MSH6 in DNA repair and intestinal tumorigenesis. Cancer research 60 11691815
2011 Conformational trapping of mismatch recognition complex MSH2/MSH3 on repair-resistant DNA loops. Proceedings of the National Academy of Sciences of the United States of America 58 21960445
2016 Crosstalk between MSH2-MSH3 and polβ promotes trinucleotide repeat expansion during base excision repair. Nature communications 48 27546332
1996 Genomic organization and expression of the human MSH3 gene. Genomics 48 8838312
2011 Association of low-risk MSH3 and MSH2 variant alleles with Lynch syndrome: probability of synergistic effects. International journal of cancer 47 21128252
2012 MSH3-deficiency initiates EMAST without oncogenic transformation of human colon epithelial cells. PloS one 46 23209772
2000 Genetic analysis of mouse embryonic stem cells bearing Msh3 and Msh2 single and compound mutations. Molecular and cellular biology 44 10594017
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
2023 Di-valent siRNA-mediated silencing of MSH3 blocks somatic repeat expansion in mouse models of Huntington's disease. Molecular therapy : the journal of the American Society of Gene Therapy 41 37177784
2014 Mispair-specific recruitment of the Mlh1-Pms1 complex identifies repair substrates of the Saccharomyces cerevisiae Msh2-Msh3 complex. The Journal of biological chemistry 41 24550389
2013 MSH3 mismatch repair protein regulates sensitivity to cytotoxic drugs and a histone deacetylase inhibitor in human colon carcinoma cells. PloS one 39 23724141
2012 Msh2-Msh3 interferes with Okazaki fragment processing to promote trinucleotide repeat expansions. Cell reports 39 22938864
2006 Effective oligonucleotide-mediated gene disruption in ES cells lacking the mismatch repair protein MSH3. Gene therapy 37 16437133
2017 MutSβ abundance and Msh3 ATP hydrolysis activity are important drivers of CTG•CAG repeat expansions. Nucleic acids research 35 28973443
2007 Chimeric Saccharomyces cerevisiae Msh6 protein with an Msh3 mispair-binding domain combines properties of both proteins. Proceedings of the National Academy of Sciences of the United States of America 34 17573527
1995 Loss of expression of the human MSH3 gene in hematological malignancies. Biochemical and biophysical research communications 34 7669036
2010 Functional studies and homology modeling of Msh2-Msh3 predict that mispair recognition involves DNA bending and strand separation. Molecular and cellular biology 31 20421420
2009 The nucleotide binding dynamics of human MSH2-MSH3 are lesion dependent. Nature structural & molecular biology 31 19377479
1997 Differential effects of the mismatch repair genes MSH2 and MSH3 on homeologous recombination in Saccharomyces cerevisiae. Molecular & general genetics : MGG 31 9439571
2008 Mismatch repair gene MSH3 polymorphism is associated with the risk of sporadic prostate cancer. The Journal of urology 29 18355840
2015 MSH3 Promotes Dynamic Behavior of Trinucleotide Repeat Tracts In Vivo. Genetics 28 25969461
2019 Contribution to colonic polyposis of recently proposed predisposing genes and assessment of the prevalence of NTHL1- and MSH3-associated polyposes. Human mutation 26 31243857
2019 Inflammation-Associated Microsatellite Alterations Caused by MSH3 Dysfunction Are Prevalent in Ulcerative Colitis and Increase With Neoplastic Advancement. Clinical and translational gastroenterology 26 31789935
2020 The Human DNA Mismatch Repair Protein MSH3 Contains Nuclear Localization and Export Signals That Enable Nuclear-Cytosolic Shuttling in Response to Inflammation. Molecular and cellular biology 25 32284349
2025 Antisense oligonucleotide-mediated MSH3 suppression reduces somatic CAG repeat expansion in Huntington's disease iPSC-derived striatal neurons. Science translational medicine 24 39937881
2007 Ninety-six haploid yeast strains with individual disruptions of open reading frames between YOR097C and YOR192C, constructed for the Saccharomyces genome deletion project, have an additional mutation in the mismatch repair gene MSH3. Genetics 24 17947417
2005 Opposing roles for DNA structure-specific proteins Rad1, Msh2, Msh3, and Sgs1 in yeast gene targeting. The EMBO journal 24 15920474
1998 Analysis of in vivo correction of defined mismatches in the DNA mismatch repair mutants msh2, msh3 and msh6 of Saccharomyces cerevisiae. Molecular & general genetics : MGG 24 9520271
2011 An MSI tumor specific frameshift mutation in a coding microsatellite of MSH3 encodes for HLA-A0201-restricted CD8+ cytotoxic T cell epitopes. PloS one 23 22110587
1998 Analysis of MSH3 in endometrial cancers with defective DNA mismatch repair. Journal of the Society for Gynecologic Investigation 23 9699180
2023 MSH2-MSH3 promotes DNA end resection during homologous recombination and blocks polymerase theta-mediated end-joining through interaction with SMARCAD1 and EXO1. Nucleic acids research 21 37140056
2014 Aberrant methylation of the MSH3 promoter and distal enhancer in esophageal cancer patients exposed to first-hand tobacco smoke. Journal of cancer research and clinical oncology 18 24934723
2021 Prevalence and Characterization of Biallelic and Monoallelic NTHL1 and MSH3 Variant Carriers From a Pan-Cancer Patient Population. JCO precision oncology 17 34250384
1999 MSH3 deficiency is not sufficient for a mutator phenotype in Chinese hamster ovary cells. Carcinogenesis 17 10069456
2017 Loss of MSH2 and MSH6 due to heterozygous germline defects in MSH3 and MSH6. Familial cancer 16 28528517
2001 Requirement for Msh6, but not for Swi4 (Msh3), in Msh2-dependent repair of base-base mismatches and mononucleotide loops in Schizosaccharomyces pombe. Genetics 16 11333218
2018 Associations of Genetic Variations in Mismatch Repair Genes MSH3 and PMS1 with Acute Adverse Events and Survival in Patients with Rectal Cancer Receiving Postoperative Chemoradiotherapy. Cancer research and treatment 14 30590005
2013 MSH3 expression does not influence the sensitivity of colon cancer HCT116 cell line to oxaliplatin and poly(ADP-ribose) polymerase (PARP) inhibitor as monotherapy or in combination. Cancer chemotherapy and pharmacology 14 23636450
2013 Distinct requirements within the Msh3 nucleotide binding pocket for mismatch and double-strand break repair. Journal of molecular biology 13 23458407
2024 Dose-dependent reduction of somatic expansions but not Htt aggregates by di-valent siRNA-mediated silencing of MSH3 in HdhQ111 mice. Scientific reports 12 38267530
2023 Novel insights into the ecDNA formation mechanism involving MSH3 in methotrexate‑resistant human colorectal cancer cells. International journal of oncology 12 37888748
2022 SYVN1-mediated ubiquitination and degradation of MSH3 promotes the apoptosis of lens epithelial cells. The FEBS journal 12 35334159
2020 Prerecognition Diffusion Mechanism of Human DNA Mismatch Repair Proteins along DNA: Msh2-Msh3 versus Msh2-Msh6. Biochemistry 12 33319999
2014 ATP binding and hydrolysis by Saccharomyces cerevisiae Msh2-Msh3 are differentially modulated by mismatch and double-strand break repair DNA substrates. DNA repair 12 24746922
2022 A large family with MSH3-related polyposis. Familial cancer 11 35675019
2015 Correlation of MSH3 polymorphisms with response and survival in advanced non-small cell lung cancer patients treated with first-line platinum-based chemotherapy. Genetics and molecular research : GMR 11 25966119
2006 DHFR and MSH3 co-amplification in childhood acute lymphoblastic leukaemia, in vitro and in vivo. Carcinogenesis 11 17148505
2019 Elevated Microsatellite Alterations at Selected Tetranucleotides (EMAST) Is Not Attributed to MSH3 Loss in Stage I-III Colon cancer: An Automated, Digitalized Assessment by Immunohistochemistry of Whole Slides and Hot Spots. Translational oncology 10 31677491
2012 Association between mismatch repair gene MSH3 codons 1036 and 222 polymorphisms and sporadic prostate cancer in the Iranian population. Asian Pacific journal of cancer prevention : APJCP 10 23464402
2024 Compound heterozygous MSH3 germline variants and associated tumor somatic DNA mismatch repair dysfunction. NPJ precision oncology 9 38243056
2023 MSH3: a confirmed predisposing gene for adenomatous polyposis. Journal of medical genetics 9 37402566
2018 Coordination of Rad1-Rad10 interactions with Msh2-Msh3, Saw1 and RPA is essential for functional 3' non-homologous tail removal. Nucleic acids research 9 29660012
2017 Inactivation of MSH3 by promoter methylation correlates with primary tumor stage in nasopharyngeal carcinoma. International journal of molecular medicine 9 28656302
2011 The mouse mismatch repair protein, MSH3, is a nucleoplasmic protein that aggregates into denser nuclear bodies under conditions of stress. Journal of cellular biochemistry 9 21344488
2024 Msh3 and Pms1 Set Neuronal CAG-repeat Migration Rate to Drive Selective Striatal and Cortical Pathogenesis in HD Mice. bioRxiv : the preprint server for biology 6 39026894
2023 A novel quantitative trait locus implicates Msh3 in the propensity for genome-wide short tandem repeat expansions in mice. Genome research 6 37127331
2021 Variant profiling of colorectal adenomas from three patients of two families with MSH3-related adenomatous polyposis. PloS one 6 34843512
1999 Genomic amplification of the human DHFR/MSH3 locus remodels mismatch recognition and repair activities. Advances in enzyme regulation 6 10470370
1999 Cloning of rat MLH1 and expression analysis of MSH2, MSH3, MSH6, and MLH1 during spermatogenesis. Genomics 6 10644444
2023 Elevated MSH2 MSH3 expression interferes with DNA metabolism in vivo. Nucleic acids research 5 37930834
2022 MSH3 Homology and Potential Recombination Link to SARS-CoV-2 Furin Cleavage Site. Frontiers in virology (Lausanne, Switzerland) 5 39176223
2000 Mutation spectrum of MSH3-deficient HHUA/chr.2 cells reflects in vivo activity of the MSH3 gene product in mismatch repair. Mutation research 5 10751599
1999 Chromosomal location and genetic mapping of the mismatch repair gene homologs MSH2, MSH3, and MSH6 in rye and wheat. Genome 4 10659795
2025 Msh2-Msh3 DNA-binding is not sufficient to promote trinucleotide repeat expansions in Saccharomyces cerevisiae. Genetics 3 39790027
2024 High-throughput sequencing and in-silico analysis confirm pathogenicity of novel MSH3 variants in African American colorectal cancer. Neoplasia (New York, N.Y.) 3 38281411
2021 Conformational distortions induced by periodically recurring A…A in d(CAG).d(CAG) provide stereochemical rationale for the trapping of MSH2.MSH3 in polyQ disorders. Computational and structural biotechnology journal 3 34471491
2017 Schizosaccharomyces pombe MutSα and MutLα Maintain Stability of Tetra-Nucleotide Repeats and Msh3 of Hepta-Nucleotide Repeats. G3 (Bethesda, Md.) 3 28341698
2025 MSH3 is a genetic modifier of somatic repeat instability in X-linked dystonia parkinsonism. bioRxiv : the preprint server for biology 2 40463055

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