Affinage

MSH3

DNA mismatch repair protein Msh3 · UniProt P20585

Length
1137 aa
Mass
127.4 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MSH3 is a core component of the DNA mismatch repair machinery that, as a heterodimer with MSH2 (MutSβ), recognizes insertion/deletion mispairs, heteroduplex loops, and branched DNA structures at double-strand/single-strand junctions, thereby maintaining genomic stability and suppressing tumorigenesis (PMID:8600025, PMID:8782829, PMID:16781730). Upon mispair binding, MutSβ adopts a distinctive nucleotide signature (ADP in MSH2, empty MSH3) and MSH3 ATPase-driven hydrolysis triggers sliding clamp formation and recruitment of downstream MutL complexes (MLH1–PMS1 and MLH1–MLH3), with MSH3's mispair-binding domain conferring substrate specificity for loops over base–base mismatches (PMID:19377479, PMID:24550389, PMID:17573527). MutSβ also participates in removal of nonhomologous 3ʹ flaps during double-strand break repair via the RAD1/RAD10 pathway and sensitizes cells to interstrand crosslink agents and PARP inhibitors when absent (PMID:9256462, PMID:21285347, PMID:24556366). Critically, MutSβ binding to CAG-hairpin DNA traps the complex in an ATPase-inhibited state that, in cooperation with pol β in base excision repair, redirects repair toward trinucleotide repeat expansion—a process dependent on both MSH3 protein levels and ATPase activity (PMID:16025128, PMID:27546332, PMID:28973443).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1996 High

    Establishing that MSH3 forms the MutSβ heterodimer with MSH2 and recognizes insertion/deletion mispairs—but not base–base mismatches—resolved how eukaryotic mismatch repair achieves substrate specialization through two parallel MSH2-containing complexes.

    Evidence Purification of yeast MSH2–MSH3; DNA binding assays with defined mispairs; genetic epistasis in msh2/msh3/msh6 mutants; chromosome transfer restoring repair in MSH3-deficient cancer cells

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

    Open questions at the time
    • Structural basis for loop vs. base–base mispair discrimination not yet resolved
    • Nucleotide requirements for mispair recognition uncharacterized
  2. 1997 High

    Demonstrating that MLH1–PMS1 stimulates MutSβ mismatch binding defined the first downstream coupling step, showing MutSβ does not act alone in lesion signaling.

    Evidence Purified yeast MLH1–PMS1; EMSA measuring stimulation of MSH2–MSH3 binding to mismatches

    PMID:9368761

    Open questions at the time
    • Mechanism of stimulation (conformational change vs. stabilization) not resolved
    • Whether MLH1–MLH3 acts similarly was unknown
  3. 1996 High

    Revealing that MSH3 (with MSH2) is required for removal of nonhomologous 3ʹ tails during double-strand break repair, epistatic with Rad1–Rad10, established a second, non-MMR function for MSH3.

    Evidence Yeast DSB repair assays in msh2/msh3/msh6/rad1/rad10 single and combination mutants

    PMID:8849883 PMID:9256462

    Open questions at the time
    • Whether MSH3 directly recruits Rad1–Rad10 or acts at a separate step was unclear
    • Biochemical reconstitution of the flap removal reaction not yet performed
  4. 1998 High

    Showing that MSH3 overexpression sequesters MSH2 and depletes MutSα explained how MSH3 dosage imbalance causes pathway-specific repair defects, establishing stoichiometric competition as a regulatory principle.

    Evidence MMR-deficient cell extract complementation; Western blotting in cells with MSH3 amplification

    PMID:9560383 PMID:9671718

    Open questions at the time
    • Transcriptional vs. post-translational regulation of MSH3 levels not addressed
    • In vivo relevance of MSH3 overexpression in tumors not established
  5. 1998 High

    Identifying MLH3 as a specific partner of MLH1 that functions in the MSH3-dependent pathway expanded the MutL repertoire and showed that MutSβ can signal through either MLH1–PMS1 or MLH1–MLH3.

    Evidence Genetic epistasis in mlh3/msh3/msh6 yeast mutants; two-hybrid MLH3–MLH1 interaction

    PMID:9770499

    Open questions at the time
    • Direct biochemical reconstitution of MLH1–MLH3 with MutSβ not yet performed
    • Relative contributions of MLH1–PMS1 vs. MLH1–MLH3 downstream of MutSβ unknown
  6. 2000 High

    MSH3 knockout mice confirmed insertion/deletion-specific repair deficiency in vivo and demonstrated that combined MSH3/MSH6 loss phenocopies MSH2 or MLH1 loss for tumor predisposition, establishing MSH3 as a cooperative tumor suppressor.

    Evidence Mouse knockouts; cellular MMR assays; tumor monitoring in single and double knockouts

    PMID:10545954 PMID:10706084

    Open questions at the time
    • MSH3-specific cancer susceptibility spectrum in humans not defined
    • Whether MSH3 loss alone predisposes to cancer remained uncertain
  7. 2000 High

    Identifying a functional PCNA-binding motif in MSH3 that is required for mismatch repair linked MutSβ to replication-associated repair initiation.

    Evidence Peptide–PCNA binding assays; PIP-box alanine mutagenesis in yeast; inhibition of MMR in human cell extracts

    PMID:11005803

    Open questions at the time
    • Whether PCNA interaction is required for DSB repair or only MMR not tested
    • Structural details of the PCNA–MutSβ interface unresolved
  8. 2005 High

    Discovering that CAG-hairpin DNA inhibits MutSβ ATPase activity and alters nucleotide occupancy provided a molecular mechanism for how MSH3 misdirects repair toward trinucleotide repeat expansion.

    Evidence Purified human MSH2–MSH3; ATPase and nucleotide binding assays on CAG-hairpin substrates

    PMID:16025128

    Open questions at the time
    • In vivo confirmation that ATPase inhibition drives expansion not yet shown
    • Downstream repair factors engaged at trapped complexes unidentified
  9. 2006 High

    Biochemical demonstration that MutSβ binds 3ʹ-tailed branched DNA at the ds/ss junction with ATP-stimulated release provided the first reconstituted evidence for its DSB repair substrate recognition mechanism.

    Evidence EMSA, ATP-release assays, and chemical footprinting with purified yeast MSH2–MSH3 on branched substrates

    PMID:16781730

    Open questions at the time
    • Reconstitution of full flap removal with Rad1–Rad10 not achieved
    • Human MutSβ behavior on branched substrates not tested
  10. 2007 High

    Domain-swap experiments proved that MSH3's mispair-binding domain (domain I) is both necessary and sufficient to confer loop/IDL specificity, resolving the structural basis for MutSβ vs. MutSα substrate discrimination.

    Evidence MSH6 chimera with MSH3 domain I; genetic and biochemical assays in yeast; MSH2 domain I deletion analysis

    PMID:17157869 PMID:17573527 PMID:17636021

    Open questions at the time
    • Crystal structure of MutSβ bound to an IDL substrate not available
    • How domain I communicates with the ATPase domain at the atomic level unknown
  11. 2009 High

    Determining the nucleotide occupancy cycle of each MutSβ subunit upon loop binding—ADP/empty → ATP hydrolysis in MSH3 driving ADP release from MSH2—established a subunit-specific ATPase mechanism distinct from MutSα.

    Evidence Fluorescence-based nucleotide binding and hydrolysis assays with purified human MSH2–MSH3

    PMID:19377479

    Open questions at the time
    • How this nucleotide cycle couples to sliding clamp formation not directly shown
    • Structural snapshots of nucleotide states unavailable
  12. 2011 High

    Single-molecule and biophysical analyses showed MutSβ discriminates repair-competent loops from pathogenic CAG hairpins by sensing junction dynamics—trapping on hairpins explains expansion while release from normal loops enables repair.

    Evidence Single-molecule FRET, SAXS, and EMSA with purified MSH2–MSH3 on loop vs. hairpin substrates

    PMID:21960445

    Open questions at the time
    • Identity of the junction structural feature that traps MutSβ not defined at atomic resolution
    • Whether trapping duration correlates with expansion length in vivo unknown
  13. 2011 High

    MSH3 deficiency sensitizes cancer cells to cisplatin and PARP inhibitors independently of canonical MLH1-dependent MMR, establishing an exploitable vulnerability tied to MSH3's DSB repair role.

    Evidence Isogenic HCT116 cells with inducible MSH3 knockdown; drug sensitivity and DNA damage marker assays

    PMID:21285347

    Open questions at the time
    • Mechanism by which MSH3 promotes DSB repair downstream of crosslinks not delineated
    • Clinical relevance in MSH3-mutant patient tumors not tested
  14. 2013 High

    Identifying MSH3 protein level as a genetic modifier of somatic CAG repeat instability in congenic mice, with ATPase activity required for expansion, established MSH3 dosage as a key determinant of repeat disease progression.

    Evidence Reciprocal congenic mouse strains; MSH3 protein quantification across tissues; comparison to Msh2 knockout

    PMID:23468640

    Open questions at the time
    • Mechanism linking MSH3 protein level variation to differential expression unknown
    • Whether therapeutic MSH3 reduction could slow repeat expansion in patients untested
  15. 2014 High

    Reconstituting MutSβ-stimulated MLH1–MLH3 endonuclease activity and demonstrating MutSβ sliding clamp formation with rapid dissociation kinetics defined the complete mismatch-to-incision signaling cascade for the MutSβ pathway.

    Evidence Purified yeast Msh2–Msh3 and Mlh1–Mlh3; endonuclease assays on supercoiled DNA; sliding clamp and MLH recruitment assays with chimeric proteins

    PMID:24403070 PMID:24550389

    Open questions at the time
    • How rapid sliding clamp dissociation of MutSβ affects repair efficiency relative to MutSα unclear
    • Full reconstitution of the complete repair reaction with exonuclease and resynthesis not achieved
  16. 2016 High

    Demonstrating that MutSβ cooperates with pol β in base excision repair to convert TNR deletions into expansions established a direct mechanistic link between oxidative damage repair and repeat expansion pathology.

    Evidence In vitro BER reconstitution with purified MSH2–MSH3 and pol β on TNR substrates

    PMID:27546332

    Open questions at the time
    • Whether this BER crosstalk occurs in neuronal cells in vivo not shown
    • Relative contribution of BER vs. MMR to expansion in disease models not quantified
  17. 2017 High

    Definitive separation-of-function experiments showed that MSH3 ATPase activity is as critical as MSH3 expression level for driving CTG·CAG expansions, unifying the dosage and enzymatic requirements for expansion.

    Evidence ATPase-dead MSH3 complementation in Msh3−/− cells; overexpression; expansion and contraction assays

    PMID:28973443

    Open questions at the time
    • Therapeutic window for partial MSH3 inhibition that blocks expansion without compromising MMR undefined
    • In vivo validation in repeat expansion disease models with ATPase-selective inhibitors not performed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for MutSβ's differential processing of repair-competent loops versus pathogenic hairpins at atomic resolution, and whether selective MSH3 modulation can decouple trinucleotide repeat expansion from essential mismatch repair, remain major unresolved questions.
  • No high-resolution structure of MutSβ bound to an IDL or hairpin substrate
  • No selective MSH3 inhibitor tested for uncoupling expansion from MMR in vivo
  • Whether MSH3 participates in additional DNA repair pathways beyond MMR, DSB repair, and BER remains unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0140657 ATP-dependent activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-73894 DNA Repair 4 R-HSA-1643685 Disease 2
Partners
MLH1MLH3MSH2PCNAPMS1POLBRAD1RAD10
Complex memberships
MutSβ (MSH2–MSH3)

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 MSH3 forms a heterodimer with MSH2 (MutSβ) that specifically recognizes insertion/deletion mispairs but has low affinity for base-base mismatches (G/T), while MSH2-MSH6 (MutSα) recognizes both; MSH3 and MSH6 constitute redundant but distinct MSH2-dependent mismatch repair pathways Purification of yeast MSH2-MSH3 heterodimer to near homogeneity; DNA binding assays with defined mispair substrates; genetic epistasis in msh2, msh3, msh6 single and double mutants measuring mutation rates and spectra Genes & development / Current biology High 8600025 8631743 8805366
1996 MSH3 (and MSH2) are required for removal of nonhomologous 3' DNA ends during double-strand break repair by gene conversion and single-strand annealing, functioning in the same pathway as the Rad1-Rad10 nuclease; MSH3 recognizes branched DNA structures with free 3' tails in addition to heteroduplex loops Genetic epistasis in yeast DSB repair assays; measurement of kinetics of recombination and gene conversion in msh2, msh3, msh6, rad1, rad10 single and combination mutants Proceedings of the National Academy of Sciences / Genetics High 8849883 9256462
1998 MSH3 overexpression sequesters MSH2 into MutSβ, depleting MutSα (MSH2-MSH6) and causing degradation of partnerless MSH6, leading to a mismatch repair defect specific to base-base mispairs while loop repair by MutSβ is maintained; MSH2 is primarily complexed with MSH6 under normal stoichiometry Complementation of MMR-deficient cell extracts with recombinant hMutSα and hMutSβ; analysis of cells with DHFR-locus amplification causing MSH3 overexpression; Western blotting for MSH2/MSH3/MSH6 levels Proceedings of the National Academy of Sciences High 9671718
2000 MSH3 contains an N-terminal PCNA-binding motif (PIP box); MSH3 peptides bind PCNA directly, and alanine substitution in the motif elevates mutation rates in yeast; addition of MSH3 PIP-box peptides to human cell extracts inhibits mismatch repair at a step preceding DNA resynthesis Peptide-PCNA binding assays; site-directed mutagenesis of PIP box with alanine substitutions; yeast mutation rate assays; inhibition of MMR in human cell extracts The Journal of biological chemistry High 11005803
1997 The yeast MLH1-PMS1 heterodimer enhances mismatch recognition by MSH2-MSH3; by itself MLH1-PMS1 shows no affinity for mismatched DNA, but it greatly stimulates MSH2-MSH3 binding to DNA mismatches Purification of yeast MLH1-PMS1 to near homogeneity; electrophoretic mobility shift assays measuring MSH2-MSH3 mismatch binding in the presence and absence of MLH1-PMS1 Current biology High 9368761
1998 The Saccharomyces cerevisiae MLH3 gene functions specifically in the MSH3-dependent mismatch repair pathway for insertion/deletion mispairs; MLH3 interacts with MLH1 in a two-hybrid assay and likely acts as an MLH1-MLH3 heterodimer in place of MLH1-PMS1 for a subset of MSH3-repaired substrates Genetic epistasis using mlh3, msh3, msh6 single and double mutants measuring frameshift reversion rates; yeast two-hybrid assay for MLH3-MLH1 interaction Proceedings of the National Academy of Sciences High 9770499
2005 Human MSH2-MSH3 binds CAG-hairpin DNA (a trinucleotide repeat expansion intermediate); this binding inhibits the ATPase activity of MSH2-MSH3 and alters nucleotide (ADP and ATP) affinity and protein-DNA binding interfaces, depending on A.A mispairs in the hairpin stem — producing functional defects that could misdirect repair toward expansion In vitro binding assays with purified protein and synthetic CAG-hairpin DNA substrates; ATPase activity measurements; nucleotide binding competition assays Nature structural & molecular biology High 16025128
2006 Yeast MSH2-MSH3 specifically binds branched DNA substrates containing 3' single-stranded DNA tails (predicted intermediates of single-strand annealing and gene conversion); ATP stimulates release of MSH2-MSH3 from these substrates; chemical footprinting shows MSH2-MSH3 binds at the double-strand/single-strand junction and alters conformation of the junction Electrophoretic mobility shift assays with defined branched DNA substrates; ATP-stimulated release experiments; chemical footprinting analyses Journal of molecular biology High 16781730
2006 Domain I (mispair binding domain) of MSH2 contributes non-specific DNA binding activity to the MSH2-MSH3 complex, while domain I of MSH3 confers mispair binding specificity and suppresses non-specific DNA binding; deletion of MSH2 domain I selectively abolishes MSH2-MSH3-mediated MMR while leaving MSH2-MSH6-mediated MMR largely intact Genetic separation-of-function analysis using msh2Δ1 allele in yeast; biochemical mispair binding assays with purified MSH2-MSH3 complexes; domain chimera constructs Journal of molecular biology High 17157869
2007 Yeast Msh2-Msh3 exhibits robust binding to specific base-base mispairs (GC to CG, AT to TA transversions) in addition to insertion/deletion mispairs; msh3 mutants show altered base substitution spectra and accumulate homology-mediated duplication/deletion mutations; the Mlh1-Mlh3 heterodimer parallels Msh2-Msh3 in these functions CAN1 forward mutation assay to measure rates and spectra in msh3 mutants; purification of Msh2-Msh3; mispair binding analysis with substrates derived from in vivo CAN1 mutational sequences Molecular and cellular biology High 17636021
2007 A chimeric Msh6 protein in which its mispair-binding domain was replaced by the equivalent domain of Msh3 conferred Msh3-like mispair-binding specificity while retaining Msh6-like properties for MutL interactions, demonstrating that Msh3's mispair-binding domain determines substrate specificity and that communication between the mispair-binding domain and ATPase domain is conserved between MSH2-MSH3 and MSH2-MSH6 Construction of chimeric Msh6 with Msh3 mispair-binding domain; genetic assays in yeast; biochemical and genetic interaction assays with MutL homologs Proceedings of the National Academy of Sciences High 17573527
2009 Human MSH2-MSH3 recognizes DNA loops by a nucleotide-binding mechanism distinct from MSH2-MSH6: upon loop binding, MSH2-MSH3 adopts a specific 'nucleotide signature' with ADP in MSH2 and an empty MSH3 subunit; ATP binding and hydrolysis in MSH3 then promotes ADP-ATP exchange in MSH2 to yield an ATP-MSH2-MSH3-ADP intermediate; ADP release from DNA-bound MSH2-MSH3 requires ATP hydrolysis in MSH3 (opposite to MSH2-MSH6 which requires ATP stabilization) Nucleotide binding and hydrolysis assays with purified human MSH2-MSH3; fluorescence and biochemical measurements of nucleotide occupancy at each subunit upon DNA loop binding Nature structural & molecular biology High 19377479
2011 MSH2/MSH3 discriminates between repair-competent and repair-resistant DNA loops by sensing conformational dynamics at their junctions; MSH2/MSH3 binds, bends, and dissociates from repair-competent loops to signal repair, but is conformationally trapped (inhibited in dissociation) on CAG-hairpin loops whose junction structure prevents ATP-dependent release Electrophoretic mobility shift assay; single-molecule fluorescence (FRET); small-angle X-ray scattering; biophysical analysis of MSH2/MSH3 conformational states on different DNA loop substrates Proceedings of the National Academy of Sciences High 21960445
2014 Yeast Msh2-Msh3 stimulates the endonuclease activity of Mlh1-Mlh3; purified Mlh1-Mlh3 is a metal-dependent endonuclease that makes single-strand breaks in supercoiled DNA, and this activity is stimulated by Msh2-Msh3, supporting a direct role in resolving recombination intermediates and DNA mismatch repair Purification of Mlh1-Mlh3 and Msh2-Msh3; endonuclease assay on supercoiled DNA; stimulation assay with Msh2-Msh3 added to Mlh1-Mlh3 reactions The Journal of biological chemistry High 24403070
2014 Msh2-Msh3 forms mispair-dependent sliding clamps and recruits Mlh1-Pms1 on +1 through +4 insertion/deletions and CC, AA, and GG mispairs; the nucleotide binding and communicating regions (not the mispair binding domain) of Msh2-Msh3 are responsible for its extremely rapid dissociation of sliding clamps from DNA compared to Msh2-Msh6 Purification of S. cerevisiae Msh2-Msh3; mispair binding, sliding clamp formation, and Mlh1-Pms1 recruitment assays; Msh2-Msh6/Msh3 chimeric protein analysis; point mutant analysis The Journal of biological chemistry High 24550389
2011 MSH3 deficiency in colorectal cancer cells sensitizes them to cisplatin and oxaliplatin (interstrand cross-link-inducing agents) and to PARP inhibitor olaparib; this sensitization is independent of MLH1/canonical MMR; MSH3-deficient cells show elevated γH2AX and 53BP1 after treatment, indicating a role for MSH3 in double-strand break repair Isogenic HCT116-derived clones with Tet-off shRNA controlling MSH3 expression; cell viability assays; siRNA knockdown of MLH1; γH2AX and 53BP1 immunofluorescence The Journal of biological chemistry High 21285347
2014 MSH3 mutations create a synthetic lethal interaction with DNA-PKcs (PRKDC); MSH3-mutant cancer cell lines show non-oncogene addiction to DNA-PKcs, and DNA-PKcs inhibition induces apoptosis in MSH3-mutant cells in vitro and displays single-agent efficacy against MSH3-mutant tumors in vivo Mutational profiling of 67 cancer cell lines across 1,319 genes; DNA-PKcs inhibitor treatment of MSH3-mutant vs. wild-type cell lines; in vivo xenograft experiments; apoptosis assays Cancer discovery High 24556366
2016 MSH2-MSH3 acts as a component of the base excision repair (BER) machinery to promote trinucleotide repeat expansion; MSH2-MSH3 stimulates pol β to copy through TNR sequences 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 with purified MSH2-MSH3 and pol β on TNR substrates; measurement of pol β bypass, flap formation, and deletion vs. expansion outcomes Nature communications High 27546332
2013 MSH3 protein levels are a modifier of CAG repeat instability; B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while CBy MSH3 variant is expressed at barely detectable levels and associated with CAG stability; Msh3 ATPase activity is required for driving repeat expansions Reciprocal congenic mouse strain analysis identifying Msh3 as the genetic determinant; MSH3 protein level measurements; comparison to Msh2 knockout stabilization PLoS genetics High 23468640
2017 MutSβ abundance (MSH2-MSH3 heterodimer level) and Msh3 ATPase hydrolysis activity are both critical drivers of CTG·CAG repeat expansions; an ATPase-defective Msh3 expressed at normal levels is as defective for expansions as Msh3-null cells; Msh3 overexpression leads to elevated MutSβ and high expansion activity Msh3 ATPase mutant complementation in Msh3-/- cells; overexpression constructs; CTG·CAG repeat expansion assays; contraction assays as control Nucleic acids research High 28973443
1998 Human MutSβ (hMSH2/hMSH3) repairs insertion-deletion loops but not base/base mispairs, while MutSα (hMSH2/hMSH6) repairs both; hMSH3 and hMSH6 share partially redundant roles in repair of replication errors including base-base mismatches and 1-4 extra bases Complementation of MMR-deficient HEC59 cell extracts with purified recombinant hMutSα and hMutSβ; microsatellite instability and HPRT mutation rate analysis in HHUA cells with chromosome 5 (MSH3) or chromosome 2 (MSH6) transfer Genetics High 9560383
2000 Mouse Msh3 deficiency causes defective repair of insertion/deletion mismatches but not base-base mismatches; combined Msh3 and Msh6 deficiency produces a tumor predisposition phenotype indistinguishable from Msh2 or Mlh1 knockout, demonstrating cooperative tumor suppression Mouse knockout of Msh3; mismatch repair assays on Msh3-/- cells; tumor incidence monitoring in Msh3-/-, Msh6-/-, and Msh3/Msh6 double-knockout mice Cancer research / Nature genetics High 10545954 10706084
2000 MSH2-MSH3 (MutSβ) but not MSH2-MSH6 (MutSα) is required for modulation of somatic hypermutation base substitution patterns at immunoglobulin loci; Msh6 deficiency shifts mutations to G/C bases, while Msh3 deficiency has no effect on hypermutation patterns Sequencing of V and S regions from Msh3-/- and Msh6-/- mice; comparison of mutation positions and base identities between genotypes The Journal of experimental medicine / The Journal of experimental medicine High 10662804 15238605
1996 MSH3 frameshift mutation in an endometrial carcinoma cell line causes deficiency in repair of DNA substrates containing mismatches or extra nucleotides; introduction of chromosome 5 (encoding MSH3) into mutant cells restored repair of specific extra-nucleotide substrates, demonstrating that MSH3 encodes a functional mismatch repair protein with substrate specificity for heteroduplex loops Mutation screening; MMR repair assays in cell extracts; microcell-mediated chromosome transfer to restore MSH3 expression; microsatellite stability assays Nature genetics High 8782829

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 501 8600025
1999 Structural, mechanistic and clinical aspects of MRP1. Biochimica et biophysica acta 332 10581367
2017 Structural Basis of Substrate Recognition by the Multidrug Resistance Protein MRP1. Cell 298 28238471
2006 Transport of glutathione and glutathione conjugates by MRP1. Trends in pharmacological sciences 282 16820223
2014 Multidrug resistance protein 1 (MRP1, ABCC1), a "multitasking" ATP-binding cassette (ABC) transporter. The Journal of biological chemistry 275 25281745
1998 Functional multidrug resistance protein (MRP1) lacking the N-terminal transmembrane domain. The Journal of biological chemistry 271 9822694
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
2013 Targeting multidrug resistance protein 1 (MRP1, ABCC1): past, present, and future. Annual review of pharmacology and toxicology 266 24050699
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
1999 ATP- and glutathione-dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1. British journal of pharmacology 229 10188979
1997 Transport of glutathione conjugates and glucuronides by the multidrug resistance proteins MRP1 and MRP2. Biological chemistry 213 9377473
2001 Mutant p53 cooperates with ETS and selectively up-regulates human MDR1 not MRP1. The Journal of biological chemistry 200 11483599
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 182 27476653
2000 Functional interaction of proliferating cell nuclear antigen with MSH2-MSH6 and MSH2-MSH3 complexes. The Journal of biological chemistry 181 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 176 9671718
2007 Role of the MRP1/ABCC1 multidrug transporter protein in cancer. IUBMB life 172 18085475
1996 Requirement of the yeast MSH3 and MSH6 genes for MSH2-dependent genomic stability. The Journal of biological chemistry 170 8631743
2002 Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1. Biochimica et biophysica acta 167 12084474
1996 Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair. Nature genetics 164 8782829
1990 Nonpeptide angiotensin II receptor antagonists. Studies with EXP9270 and DuP 753. Hypertension (Dallas, Tex. : 1979) 159 2351436
2005 Expression of drug resistance proteins Pgp, MRP1, MRP3, MRP5 and GST-pi in human glioma. Journal of neuro-oncology 157 16193381
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
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 134 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 128 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
1998 Excretion of GSSG and glutathione conjugates mediated by MRP1 and cMOAT/MRP2. Seminars in liver disease 126 9875554
2008 The inv dup (15) or idic (15) syndrome (Tetrasomy 15q). Orphanet journal of rare diseases 125 19019226
2004 Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1). Proceedings of the National Academy of Sciences of the United States of America 118 14983033
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 108 24403070
1991 In vivo pharmacology of DuP 753. American journal of hypertension 107 1854454
2004 Verapamil and its derivative trigger apoptosis through glutathione extrusion by multidrug resistance protein MRP1. Cancer research 106 15256468
2017 USP22 mediates the multidrug resistance of hepatocellular carcinoma via the SIRT1/AKT/MRP1 signaling pathway. Molecular oncology 91 28417539
2003 Role of MDR1 and MRP1 in trophoblast cells, elucidated using retroviral gene transfer. American journal of physiology. Cell physiology 91 12724138
1998 Motility related protein 1 (MRP1/CD9) expression in colon cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 91 9626469
1991 Nonpeptide angiotensin II receptor antagonists. Studies with DuP 753 and EXP3174 in dogs. European journal of pharmacology 87 1748155
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
2005 The inv dup(15) or idic(15) syndrome: a clinically recognisable neurogenetic disorder. Brain & development 75 16023554
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
2005 Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters. Pharmacogenetics and genomics 73 16006996
2001 Identification of human multidrug resistance protein 1 (MRP1) mutations and characterization of a G671V substitution. Journal of human genetics 71 11721885
1991 In vitro pharmacology of DuP 753. American journal of hypertension 70 1854453
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