Affinage

MSH6

DNA mismatch repair protein Msh6 · UniProt P52701

Length
1360 aa
Mass
152.8 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MSH6 is the mismatch-recognition subunit of the eukaryotic DNA mismatch repair (MMR) machinery, functioning as an obligate heterodimer with MSH2 (the MutSα complex) that initiates correction of replication errors (PMID:7604265, PMID:7604266, PMID:8600025, PMID:8723353, PMID:8631743). Within this heterodimer MSH6 makes the base-specific contact with mispaired DNA through a conserved phenylalanine, whose substitution abolishes mismatch binding without disrupting heterodimerization (PMID:10347163); the two subunits are functionally asymmetric, with MSH6 acting as the rapid ATPase whose mismatch binding suppresses its own ATP hydrolysis ('cis' coupling) to drive the complex into an ATP-bound state (PMID:16214425). ATP binding converts the mispair-bound complex into a rapidly diffusing sliding clamp, a two-state mechanism resolved by both real-time and single-molecule analyses (PMID:15811858, PMID:16337600). MSH6 carries an N-terminal PIP box that recruits PCNA, localizing the complex to replication sites and activating the Mlh1-Pms1 endonuclease for downstream excision; mismatch recognition transiently releases PCNA, supporting an ordered handoff to the mispair (PMID:11005803, PMID:12435741, PMID:24981171). Genetically, MSH6 loss specifically abolishes single-base mismatch repair while insertion/deletion repair persists through the redundant MSH2-MSH3 pathway, producing mononucleotide-repeat instability, and combined loss of MSH3 and MSH6 phenocopies MSH2 deficiency (PMID:7604266, PMID:9390556, PMID:10545954, PMID:10706084). Beyond replication-error correction, the MSH2-MSH6 heterodimer drives the A:T-mutation phase of immunoglobulin somatic hypermutation and class-switch recombination (PMID:10662804, PMID:15238605, PMID:16618598), contributes to UV-B-induced apoptosis (PMID:14632208), and associates with Ku70 to support non-homologous end-joining at double-strand breaks (PMID:21075794). MSH6 activity is further tuned by regulatory phosphorylation (PKC, CK2, and S6K1 at Ser309) and by lysine crotonylation at K544 that governs the MSH6-Ku70 interaction (PMID:11972333, PMID:36189922, PMID:37167869). Loss of MSH6-dependent damage sensing causally mediates resistance to temozolomide and thiopurines by failing to engage apoptotic and checkpoint responses (PMID:19584161, PMID:25078279, PMID:29449434).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1995 High

    Established that mismatch recognition in human cells requires a defined heterodimer rather than a single protein, defining MSH6's obligate partnership with MSH2.

    Evidence Biochemical purification, co-IP and gel-shift mismatch-binding assays in tumor cell lines lacking either subunit

    PMID:7604265 PMID:7604266

    Open questions at the time
    • Did not resolve which subunit contacts the mismatch
    • No structural basis for heterodimerization
  2. 1995 High

    Connected MSH6 loss to a specific genome-instability signature, showing it is not functionally interchangeable with other MMR genes.

    Evidence Microsatellite instability analysis and sequencing of inactivating mutations in hypermutable tumor lines

    PMID:7604266

    Open questions at the time
    • Mechanistic basis for mononucleotide-specific instability not yet defined
  3. 1996 High

    Showed the heterodimer mechanism is conserved and defined the division of labor between MutSα and MutSβ pathways.

    Evidence Yeast genetics (null mutants, mutation-rate assays), co-IP and biochemical mismatch-binding assays

    PMID:8600025 PMID:8631743 PMID:8723353

    Open questions at the time
    • Extent of MSH3/MSH6 redundancy in vivo not quantified at this stage
  4. 1997 High

    Demonstrated in a clean genetic system that MSH6 is specifically required for single-base mismatch correction, separating its role from insertion/deletion repair.

    Evidence Msh6-null mouse cells with cell-free mismatch repair assay on defined substrates

    PMID:9390556

    Open questions at the time
    • Did not address non-MMR functions
  5. 1999 High

    Pinpointed the residue responsible for mismatch recognition, separating DNA-contact function from heterodimer assembly.

    Evidence msh6-F337A site-directed mutagenesis with UV cross-linking, binding, ATPase assays and yeast genetics

    PMID:10347163

    Open questions at the time
    • Structural geometry of the phenylalanine-mismatch contact not directly visualized
  6. 1999 High

    Established quantitatively that MSH2-MSH6 and MSH2-MSH3 jointly cover the MSH2 pathway, while MSH6 alone governs anti-recombination and methylator sensitivity.

    Evidence Msh3/Msh6 single and double knockout mice with tumor, MMR, anti-recombination and drug-sensitivity readouts

    PMID:10545954 PMID:10706084

    Open questions at the time
    • Molecular basis of MSH6-specific anti-recombination not defined
  7. 2000 High

    Identified the PCNA-recruitment motif in MSH6 and placed it functionally upstream of DNA resynthesis.

    Evidence PIP-box peptide-PCNA binding, alanine mutagenesis, yeast mutation-rate assays and human extract MMR inhibition

    PMID:11005803

    Open questions at the time
    • Did not establish how PCNA binding couples to downstream endonuclease activation
  8. 2000 High

    Defined a non-canonical immune role: MSH2-MSH6 specifically drives the A:T-mutation phase of somatic hypermutation and class-switch recombination.

    Evidence Msh6-/- and Msh3-/- mice with Ig V-region/switch-region sequencing and antibody assays

    PMID:10662804 PMID:15238605

    Open questions at the time
    • Mechanism linking mismatch recognition to mutagenic processing not resolved
  9. 2002 High

    Revealed an ordered PCNA-to-mismatch handoff, mechanistically connecting replication-fork loading to mismatch recognition.

    Evidence In vitro gel-shift/filter-binding ternary complex assays with ATP/ATPγS

    PMID:12435741

    Open questions at the time
    • Single lab in vitro; kinetics of the handoff in vivo unknown
  10. 2002 Medium

    Introduced post-translational control of MMR, showing MSH6 phosphorylation is required for mismatch binding and damage-induced nuclear translocation.

    Evidence In vitro PKC/CK2 kinase assays, inhibitors, phosphatase treatment, binding and translocation assays

    PMID:11972333

    Open questions at the time
    • Phosphosites not mapped
    • Single lab; in vivo relevance partial
  11. 2002 Medium

    Showed MSH6 is constitutively expressed with post-transcriptional regulation, framing how MMR capacity is maintained across the cell cycle.

    Evidence Promoter luciferase reporter assays plus cell-cycle synchronization with Northern/Western blot

    PMID:11746986

    Open questions at the time
    • Post-transcriptional regulatory mechanism not identified
  12. 2001 Medium

    Linked MutSα to genome-stability functions beyond point-mutation correction by showing it suppresses gene amplification.

    Evidence PALA selection for CAD amplification with FISH in MMR-deficient human cells

    PMID:11717437

    Open questions at the time
    • Direct molecular role of MSH6 in suppressing unequal exchange not defined
    • Single lab
  13. 2003 Medium

    Established MSH6 as an effector of UV-B-induced apoptosis independent of p53-mediated induction.

    Evidence Msh6-/- vs wild-type primary MEFs with UV-B, apoptosis assays and Msh6 Western blot

    PMID:14632208

    Open questions at the time
    • Apoptotic signaling pathway downstream of MSH6 not mapped
    • Single lab
  14. 2005 High

    Provided direct mechanistic evidence for the two-state model: ATP converts the mispair-bound complex into a sliding clamp, with mispair-dependent MLH1-PMS1 recruitment.

    Evidence IAsys biosensor and single-molecule DNA-unzipping assays with end-blocking and ATP variants

    PMID:15811858 PMID:16337600

    Open questions at the time
    • In vivo lifetime of the sliding clamp state unknown
  15. 2005 High

    Defined subunit ATPase asymmetry and the 'cis' coupling rule whereby mismatch binding by MSH6 suppresses its own hydrolysis.

    Evidence ATPase-site mutagenesis with kinetic and DNA-binding analyses in yeast Msh2-Msh6

    PMID:16214425

    Open questions at the time
    • How asymmetry feeds into MLH1 activation not fully resolved
  16. 2006 Medium

    Separated MSH6's enzymatic and structural roles in immunity, identifying a scaffolding function directing AID targeting.

    Evidence Msh6TD/TD point-mutant knockin mice with SHM and CSR sequencing

    PMID:16618598

    Open questions at the time
    • Molecular basis of AID-targeting scaffolding not defined
    • Single lab
  17. 2009 High

    Established MSH6 loss as a causal driver of chemoresistance, demonstrating its role in damage-induced cytotoxic signaling.

    Evidence Matched pre/post-treatment tumor sequencing, in vitro selection, shRNA knockdown and MSH6 reconstitution

    PMID:19584161 PMID:25078279

    Open questions at the time
    • Signaling steps from MSH6 to cell death incompletely defined
  18. 2010 Medium

    Extended MSH6 function into double-strand break repair through a physical Ku70 interaction supporting NHEJ.

    Evidence Yeast two-hybrid, reciprocal co-IP, γ-H2AX foci colocalization, comet and NHEJ reporter assays with rescue

    PMID:21075794

    Open questions at the time
    • Whether this requires MSH2 heterodimer not established
    • Single lab
  19. 2012 High

    Dissected how disease-associated mutations uncouple nucleotide binding from mismatch recognition, explaining dominant repair failure.

    Evidence Reconstituted in vitro MMR, DNA-binding kinetics, ATPase and excision assays with purified mutant proteins

    PMID:22277660

    Open questions at the time
    • In vivo dominance of these mutants not tested
    • Single lab
  20. 2014 High

    Resolved how MSH6-bound PCNA activates downstream excision, placing MSH2-MSH6 as the localizer of the Mlh1-Pms1 endonuclease.

    Evidence Yeast PCNA-mutant genetic screen with epistasis plus biochemical PCNA-binding and endonuclease assays

    PMID:24981171

    Open questions at the time
    • Structural arrangement of the PCNA-MutSα-MutLα assembly not resolved
  21. 2018 Medium

    Showed MSH6 mediates thiopurine cytotoxicity through damage sensing and checkpoint/apoptosis activation rather than secondary mutagenesis.

    Evidence shRNA knockdown, IC50 assays, CHK1/γ-H2AX Western blot, MSI analysis and in vivo model

    PMID:29449434

    Open questions at the time
    • Mechanistic link from mismatch recognition to checkpoint activation not detailed
    • Single lab
  22. 2018 Medium

    Connected reduced MSH6 to a proliferative phenotype via downregulation of the ATR-Chk1 axis in pituitary tumor cells.

    Evidence siRNA knockdown with qPCR, proliferation assays in cell lines and primary cultures, tumor correlation

    PMID:29342268

    Open questions at the time
    • Direct molecular link between MSH6 and ATR transcription unknown
    • Single lab
  23. 2022 Medium

    Added a kinase-driven activation arm, showing S6K1 phosphorylates MSH6 at Ser309 to enhance MMR within a coordinated DNA-repair response.

    Evidence In vitro S6K1 kinase assay with phosphosite identification, MMR activity and cell-cycle assays

    PMID:36189922

    Open questions at the time
    • Functional validation of phospho-Ser309 in MMR limited
    • Single lab
  24. 2023 Medium

    Identified a crotonylation switch (K544) controlling the MSH6-Ku70 interaction and the choice between NHEJ and HR in meiosis.

    Evidence Fetal-ovary Msh6 disruption, K544 crotonylation-site mutation, MSH6-Ku70 co-IP and HR/NHEJ assays

    PMID:37167869

    Open questions at the time
    • Generality beyond fetal oocytes unknown
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MSH6's diverse post-translational modifications and DSB-repair/immune scaffolding functions are mechanistically integrated with its core MutSα mismatch-repair activity remains unresolved.
  • No unified structural model linking modification states to activity
  • Crosstalk between MMR, NHEJ and SHM roles undefined
  • In vivo significance of individual modification sites not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0140657 ATP-dependent activity 3 GO:0098772 molecular function regulator activity 2 GO:0140097 catalytic activity, acting on DNA 2
Localization
GO:0005634 nucleus 2 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-73894 DNA Repair 3 R-HSA-168256 Immune System 2
Partners
KU70MLH1MSH2PCNAPMS1
Complex memberships
MutSα (MSH2-MSH6)

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 MSH6 (GTBP) forms a heterodimeric mismatch-binding complex with hMSH2; both proteins are required for mismatch-specific DNA binding activity in human cells, as demonstrated by loss of binding activity in tumor cell lines lacking either protein. Biochemical purification, co-immunoprecipitation, gel-shift/mismatch-binding assays, tumor cell line analysis Science High 7604265 7604266
1996 In S. cerevisiae, MSH6 binds to DNA mismatches as a heterodimer with MSH2, mirroring the human GTBP-hMSH2 complex; yeast MSH2-MSH6 provides the primary pathway for repair of base-base and single-nucleotide insertion/deletion mismatches, while MSH2-MSH3 provides a partially redundant pathway for insertion/deletion repair. Yeast genetics (null mutations, mutation-rate assays, co-immunoprecipitation), biochemical mismatch-binding assays Genes & development / Current biology / Journal of biological chemistry High 8600025 8631743 8723353
1995 Loss-of-function mutations in GTBP/MSH6 in human tumor cell lines produce a mutator phenotype characterized primarily by instability at mononucleotide (rather than dinucleotide) repeat tracts, distinguishing it from defects in other MMR genes. Microsatellite instability analysis, gene sequencing of hypermutable tumor cell lines Science High 7604266
1997 Msh6-null mouse cells are specifically defective in repair of single-nucleotide mismatches but retain repair of 1-, 2-, and 4-nucleotide insertion/deletion mismatches, establishing that MSH6 is required for single-base mismatch correction in vivo. Gene targeting (knockout mouse), cell-free mismatch repair assay on extracts Cell High 9390556
2000 MSH3 and MSH6 contain N-terminal PCNA-binding motifs (PIP boxes) that mediate direct interaction with PCNA; mutation of conserved residues in these motifs elevates mutation rates in yeast, and addition of MSH6 or MSH3 PCNA-binding peptides to human cell extracts inhibits mismatch repair prior to DNA resynthesis. Peptide-PCNA binding assays, alanine substitution mutagenesis, yeast mutation-rate assays, human cell extract MMR inhibition assay Journal of Biological Chemistry High 11005803
2002 PCNA and MSH2-MSH6 form a stable ternary complex on homoduplex DNA, but mismatch recognition by MSH2-MSH6 disrupts its binding to PCNA; ATP or ATPγS restores PCNA binding by releasing MSH2-MSH6 from the mismatch. This supports a model in which MSH2-MSH6 is transferred from PCNA to mispaired bases. In vitro protein-DNA binding assays (gel shift, filter binding), nucleotide addition experiments Journal of Biological Chemistry High 12435741
2005 Analysis of the S. cerevisiae MSH2-MSH6 complex using a reversible DNA end-blocking system showed that ATP binding converts the mispair-bound MSH2-MSH6 into a rapidly sliding clamp that dissociates via DNA ends; MLH1-PMS1 forms mispair-dependent ternary complexes with MSH2-MSH6 in an ATP- and magnesium-dependent manner on end-blocked DNA. IAsys biosensor real-time binding assay with lac repressor-operator end-blocking system Journal of Biological Chemistry High 15811858
2005 Single-molecule DNA-unzipping force analysis of S. cerevisiae MSH2-MSH6 revealed a high-affinity mismatch-recognition state not detectable in bulk assays, and an ATP-dependent sliding clamp state on end-blocked DNA, providing direct physical evidence for the two-state model of MSH2-MSH6 action. Single-molecule DNA-unzipping force assay Molecular cell High 16337600
1999 A phenylalanine-to-alanine substitution (msh6-F337A) in the mismatch recognition domain of yeast MSH6 disrupts mismatch DNA binding by the MSH2-MSH6 heterodimer without preventing MSH2 heterodimerization, identifying this residue as critical for mismatch recognition. Site-directed mutagenesis, UV cross-linking, filter binding, gel retardation, ATPase assays, yeast genetics Journal of Biological Chemistry High 10347163
2005 ATPase activity of the S. cerevisiae Msh2-Msh6 heterodimer is asymmetric: Msh6 is the rapid ATPase subunit (analogous to MutS S1) and makes base-specific mismatch contact via a conserved phenylalanine; Msh2 is the slower ATPase and strongly influences Msh6 ATPase; mismatch binding by Msh6 suppresses its own ATP hydrolysis ('cis' coupling), placing both subunits in an ATP-bound state that alters mismatch interactions. ATPase site mutagenesis, ATPase kinetics, DNA binding assays DNA repair High 16214425
2002 MSH2 and MSH6 proteins are phosphorylated in vitro by protein kinase C and casein kinase II; in vivo phosphorylation of MSH6 (more extensively than MSH2) is required for mismatch-binding activity of the MutSα complex and for methylation-induced nuclear translocation of the repair complex. In vitro kinase assays, phosphate depletion, kinase inhibitors, phosphatase treatment, mismatch-binding assay, nuclear translocation assay Nucleic acids research Medium 11972333
2008 The N-terminal region of human MSH6 contains a PWWP domain that binds double-stranded DNA without mismatch preference; the disease-associated S144I mutation is located within the DNA-binding surface of this domain but does not abolish DNA binding in vitro. NMR structural characterization, DNA binding assays, mutagenesis Biochemistry Medium 18484749
2010 MSH6 physically interacts with Ku70 (identified by yeast two-hybrid and confirmed by co-immunoprecipitation); this interaction is enhanced by DNA double-strand break (DSB)-inducing agents; MSH6 forms nuclear foci colocalizing with γ-H2AX at DSB sites, MSH6 depletion increases persistent DSBs, and impairs non-homologous end-joining (NHEJ), which is rescued by MSH6 overexpression. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence (foci formation, γ-H2AX colocalization), comet assay, NHEJ reporter assay, clonogenic survival Nucleic acids research Medium 21075794
2014 PCNA activates the Mlh1-Pms1 endonuclease in an Exo1-independent MMR pathway; mutations disrupting the Msh2-Msh6 interaction with PCNA (via the MSH6 PIP box) are specifically defective in this pathway, demonstrating that MSH2-MSH6 localizes PCNA to repair sites to activate Mlh1-Pms1 endonuclease activity. Yeast genetics (PCNA mutant screen, epistasis), biochemical PCNA trimerization/Msh2-Msh6 binding assays, Mlh1-Pms1 endonuclease assay, Mlh1-Pms1 focus quantification Molecular cell High 24981171
2000 The MSH2-MSH6 heterodimer (but not MSH2-MSH3) is required for the second phase of somatic hypermutation that generates A:T substitutions in immunoglobulin V genes; Msh6-deficient mice show reduced A:T mutations and reduced class-switch recombination, while Msh3-deficient mice are normal. Msh6-/- and Msh3-/- mouse models, immunoglobulin V-region and switch-region sequencing, antibody response assays Journal of Experimental Medicine High 10662804 15238605
2006 Msh6 plays a scaffolding role in the first phase of somatic hypermutation (independent of its enzymatic MMR function) to direct AID targeting to WRC motifs in vivo; a Msh6 point-mutant knockin (Msh6TD/TD) that abolishes the second phase of SHM reveals that AID targeting to non-WRC motifs increases when Msh6 enzymatic activity is lost, and that Msh6 also mediates proper recombination site targeting in CSR. Msh6 point-mutant knockin mice (Msh6TD/TD), SHM sequencing, CSR analysis Immunity Medium 16618598
2009 MSH6 mutations arise in glioblastomas during temozolomide therapy (absent in matched pre-treatment tumors); in vitro temozolomide selection generates MSH6 mutations in wild-type lines; MSH6 knockdown increases temozolomide resistance and MSH6 reconstitution in MSH6-null cells restores cytotoxicity, establishing that MSH6 loss causally mediates temozolomide resistance. Matched pre/post-treatment tumor sequencing, in vitro temozolomide selection, lentiviral shRNA knockdown, MSH6 reconstitution, clonogenic survival Clinical Cancer Research High 19584161 25078279
2018 MSH6 haploinsufficiency causes thiopurine resistance by failing to recognize thioguanine-nucleotide mismatches and initiate apoptosis/cell-cycle arrest (CHK1 and γ-H2AX activation defect), rather than by generating secondary mutations; knockdown in MMR-proficient cell lines increases IC50 to 6-TG and 6-MP with increased intracellular TGN accumulation. MSH6 shRNA knockdown in cell lines, IC50 assays, CHK1/γ-H2AX Western blot, microsatellite instability analysis, in vivo treatment model Haematologica Medium 29449434
2003 Msh6-deficient primary mouse fibroblasts undergo significantly less apoptosis following UV-B irradiation compared to wild-type cells, and UV-B increases Msh6 protein levels in wild-type cells independently of p53, establishing a role for Msh6 in the UV-B-induced apoptotic response. Primary Msh6-/- and Msh6+/+ mouse embryonic fibroblasts, UV-B irradiation, apoptosis assays, Western blot for Msh6 protein Journal of Investigative Dermatology Medium 14632208
1999 Simultaneous loss of Msh3 and Msh6 in mice produces a cancer predisposition and mismatch repair deficiency equivalent to Msh2 deficiency, demonstrating that MSH2-MSH6 and MSH2-MSH3 provide fully redundant coverage of the MSH2-dependent repair pathway; Msh6 alone is required for mismatch-directed anti-recombination and sensitivity to methylating agents. Msh3-/-, Msh6-/-, and Msh3-/-Msh6-/- double-knockout mouse models; tumor incidence, MMR assays, anti-recombination assays, methylating agent sensitivity Nature genetics High 10545954 10706084
2022 S6K1 directly phosphorylates MSH6 at serine 309, enhancing mismatch repair activity; this phosphorylation event is part of a coordinated DNA repair response in which S6K1 also phosphorylates Cdk1 at serine 39 to cause G2/M arrest enabling HR repair. In vitro kinase assay (S6K1 phosphorylating MSH6), phosphosite identification, MMR activity assays, cell-cycle analysis eLife Medium 36189922
2023 Lysine crotonylation of MSH6 at K544 (Kcr) regulates its association with Ku70; mutation of K544cr impairs MSH6-Ku70 association and promotes NHEJ over homologous recombination (HR) in fetal oocytes during meiosis; DBP exposure reduces MSH6 crotonylation and mimics Msh6 knockout meiotic defects. Targeted disruption of Msh6 in fetal ovaries, K544 crotonylation site mutation, co-immunoprecipitation (MSH6-Ku70), HR/NHEJ assays, meiotic progression analysis Journal of Hazardous Materials Medium 37167869
2012 Biochemical analysis of human MSH2(G674A)-MSH6 and MSH2-MSH6(T1219D) mutants showed that both retain mismatch recognition but fail MMR in vitro by different mechanisms: MSH6(T1219D) fails to couple nucleotide binding with mismatch recognition, while MSH2(G674A) has a partial nucleotide-binding defect; both remain mismatch-bound and inhibit excision in a dominant manner. In vitro MMR assay, DNA binding kinetics, ATPase assay, excision step assay with defined mutant proteins Journal of Biological Chemistry High 22277660
2001 MSH6 deficiency (or MLH1 deficiency) elevates the rate of CAD gene amplification 50–100-fold in human cells, with amplification events occurring via unequal sister chromatid exchange and translocations, implicating MutSα in suppression of gene amplification. PALA selection for CAD amplification, FISH analysis, mismatch repair-deficient human cell lines PNAS Medium 11717437
2002 The human MSH6 promoter is a classical housekeeping gene promoter; MSH6 transcription is upregulated during late G1 phase, but protein levels remain essentially constant during the cell cycle, suggesting post-transcriptional regulation. Promoter cloning and functional luciferase reporter assays, cell-cycle synchronization with Northern/Western blot Genes, Chromosomes & Cancer Medium 11746986
2018 Reduced MSH6 (and MSH2) expression directly promotes pituitary tumor cell proliferation by decreasing ATR expression in the ATR-Chk1 pathway; siRNA-mediated knockdown of MSH6 and/or MSH2 in AtT-20ins cells and primary human pituitary adenoma cultures significantly increased cell proliferation and decreased ATR expression. siRNA knockdown, real-time qPCR, cell proliferation assays in cell lines and primary cultures, correlation analysis in human tumor specimens Journal of Clinical Endocrinology and Metabolism Medium 29342268

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
1995 Mutations of GTBP in genetically unstable cells. Science (New York, N.Y.) 489 7604266
1995 GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Science (New York, N.Y.) 484 7604265
2009 MSH6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance. Clinical cancer research : an official journal of the American Association for Cancer Research 325 19584161
1997 Mutation in the mismatch repair gene Msh6 causes cancer susceptibility. Cell 314 9390556
2009 Risks of Lynch syndrome cancers for MSH6 mutation carriers. Journal of the National Cancer Institute 295 20028993
2011 Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. International journal of cancer 254 21425258
2003 Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proceedings of the National Academy of Sciences of the United States of America 188 12732731
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
1996 Requirement of the yeast MSH3 and MSH6 genes for MSH2-dependent genomic stability. The Journal of biological chemistry 170 8631743
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
2010 The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history. Gastroenterology 151 20727894
2000 The DNA mismatch repair genes Msh3 and Msh6 cooperate in intestinal tumor suppression. Cancer research 133 10706084
2020 Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057 microsatellite instability-high solid tumors. International journal of cancer 130 32449172
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
2010 Neoadjuvant therapy induces loss of MSH6 expression in colorectal carcinoma. The American journal of surgical pathology 118 21107085
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 Analysis of the interaction between the Saccharomyces cerevisiae MSH2-MSH6 and MLH1-PMS1 complexes with DNA using a reversible DNA end-blocking system. The Journal of biological chemistry 106 15811858
2006 Somatic hypermutation and class switch recombination in Msh6(-/-)Ung(-/-) double-knockout mice. Journal of immunology (Baltimore, Md. : 1950) 97 17015724
2014 PCNA and Msh2-Msh6 activate an Mlh1-Pms1 endonuclease pathway required for Exo1-independent mismatch repair. Molecular cell 89 24981171
1996 MSH6, a Saccharomyces cerevisiae protein that binds to mismatches as a heterodimer with MSH2. Current biology : CB 89 8723353
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
1999 A mutation in the MSH6 subunit of the Saccharomyces cerevisiae MSH2-MSH6 complex disrupts mismatch recognition. The Journal of biological chemistry 81 10347163
1999 Mononucleotide microsatellite instability and germline MSH6 mutation analysis in early onset colorectal cancer. Journal of medical genetics 79 10507723
2020 Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome. Gastroenterology 78 31926173
2012 Secondary mutation in a coding mononucleotide tract in MSH6 causes loss of immunoexpression of MSH6 in colorectal carcinomas with MLH1/PMS2 deficiency. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 76 22918162
2010 MSH6 and MUTYH deficiency is a frequent event in early-onset colorectal cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 73 20924129
2002 Phosphorylation of mismatch repair proteins MSH2 and MSH6 affecting MutSalpha mismatch-binding activity. Nucleic acids research 62 11972333
2008 RNA-based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference. Human mutation 61 18030674
2001 MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer. Cancer research 61 11245474
2007 Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Human mutation 57 17557300
2014 Novel MSH6 mutations in treatment-naïve glioblastoma and anaplastic oligodendroglioma contribute to temozolomide resistance independently of MGMT promoter methylation. Clinical cancer research : an official journal of the American Association for Cancer Research 55 25078279
2004 Penetrance and expressivity of MSH6 germline mutations in seven kindreds not ascertained by family history. American journal of human genetics 54 15098177
2007 MSH-6: extending the reliability of immunohistochemistry as a screening tool in Muir-Torre syndrome. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 53 18065960
2005 The role of MLH1, MSH2 and MSH6 in the development of multiple colorectal cancers. British journal of cancer 53 16106253
2010 Mismatch-repair protein MSH6 is associated with Ku70 and regulates DNA double-strand break repair. Nucleic acids research 52 21075794
2013 DNA mismatch repair gene MSH6 implicated in determining age at natural menopause. Human molecular genetics 50 24357391
2003 MSH6 germline mutations are rare in colorectal cancer families. International journal of cancer 48 14520694
2005 Detection of high-affinity and sliding clamp modes for MSH2-MSH6 by single-molecule unzipping force analysis. Molecular cell 47 16337600
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
2008 Human mismatch repair protein MSH6 contains a PWWP domain that targets double stranded DNA. Biochemistry 44 18484749
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
2018 MSH6 haploinsufficiency at relapse contributes to the development of thiopurine resistance in pediatric B-lymphoblastic leukemia. Haematologica 41 29449434
2001 High rate of CAD gene amplification in human cells deficient in MLH1 or MSH6. Proceedings of the National Academy of Sciences of the United States of America 40 11717437
2009 Constitutional mismatch repair deficiency and childhood leukemia/lymphoma--report on a novel biallelic MSH6 mutation. Haematologica 39 20015892
2008 Alkylation-induced colon tumorigenesis in mice deficient in the Mgmt and Msh6 proteins. Oncogene 39 19029948
2007 Genetic investigation of DNA-repair pathway genes PMS2, MLH1, MSH2, MSH6, MUTYH, OGG1 and MTH1 in sporadic colon cancer. International journal of cancer 39 17417778
2000 Do MSH6 mutations contribute to double primary cancers of the colorectum and endometrium? Human genetics 38 11153917
2008 Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. Familial cancer 37 18566915
2019 Oncogenic MSH6-CXCR4-TGFB1 Feedback Loop: A Novel Therapeutic Target of Photothermal Therapy in Glioblastoma Multiforme. Theranostics 36 30867843
2010 MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hereditary cancer in clinical practice 36 20487569
2003 Loss of expression of MLH1, MSH2, MSH6, and PTEN related to endometrial cancer in 68 patients with endometrial hyperplasia. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 36 12649668
2005 Contribution of Msh2 and Msh6 subunits to the asymmetric ATPase and DNA mismatch binding activities of Saccharomyces cerevisiae Msh2-Msh6 mismatch repair protein. DNA repair 35 16214425
2002 DNA binding properties of the yeast Msh2-Msh6 and Mlh1-Pms1 heterodimers. Biological chemistry 34 12222686
2006 The mismatch repair protein Msh6 influences the in vivo AID targeting to the Ig locus. Immunity 32 16618598
2005 Mismatch repair genes (hMLH1, hPMS1, hPMS2, GTBP/hMSH6, hMSH2) in the pathogenesis of hepatocellular carcinoma. World journal of gastroenterology 32 15918183
2012 Biochemical analysis of the human mismatch repair proteins hMutSα MSH2(G674A)-MSH6 and MSH2-MSH6(T1219D). The Journal of biological chemistry 30 22277660
2020 MSH6/2 and PD-L1 Expressions Are Associated with Tumor Growth and Invasiveness in Silent Pituitary Adenoma Subtypes. International journal of molecular sciences 29 32325698
1996 Molecular cloning of the N-terminus of GTBP. Genomics 29 8838326
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
2017 Neoadjuvant therapy in microsatellite-stable colorectal carcinoma induces concomitant loss of MSH6 and Ki-67 expression. Human pathology 27 28232158
2016 WT1, MSH6, GATA5 and PAX5 as epigenetic oral squamous cell carcinoma biomarkers - a short report. Cellular oncology (Dordrecht, Netherlands) 27 27491556
2020 MSH2 and MSH6 in Mismatch Repair System Account for Soybean (Glycine max (L.) Merr.) Tolerance to Cadmium Toxicity by Determining DNA Damage Response. Journal of agricultural and food chemistry 26 31971785
2023 Maternal exposure to dibutyl phthalate regulates MSH6 crotonylation to impair homologous recombination in fetal oocytes. Journal of hazardous materials 25 37167869
2008 Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than hereditary non polyposis colorectal cancer cohorts. The Ulster medical journal 25 18269114
2001 Mutations of the 'minor' mismatch repair gene MSH6 in typical and atypical hereditary nonpolyposis colorectal cancer. Familial cancer 25 14574004
2018 Up-regulation of MSH6 is associated with temozolomide resistance in human glioblastoma. Biochemical and biophysical research communications 24 29366782
2018 Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome. Cancer medicine 24 29575718
2017 MGMT and MSH6 immunoexpression for functioning pituitary macroadenomas. Pituitary 24 28900805
2016 Association of MSH6 mutation with glioma susceptibility, drug resistance and progression. Molecular and clinical oncology 24 27446556
2009 Deciphering the mismatch recognition cycle in MutS and MSH2-MSH6 using normal-mode analysis. Biophysical journal 24 19254532
2003 DNA mismatch repair protein Msh6 is required for optimal levels of ultraviolet-B-induced apoptosis in primary mouse fibroblasts. The Journal of investigative dermatology 23 14632208
1999 Induction of two DNA mismatch repair proteins, MSH2 and MSH6, in differentiated human neuroblastoma SH-SY5Y cells exposed to doxorubicin. Journal of neurochemistry 23 10037468
1999 hMSH2 and GTBP expression in advanced stage epithelial ovarian cancer. British journal of cancer 23 10408416
2014 Expression of DNA mismatch repair proteins MLH1, MSH2, and MSH6 in recurrent glioblastoma. Neurological research 22 24995467
2022 S6K1 phosphorylates Cdk1 and MSH6 to regulate DNA repair. eLife 21 36189922
2022 Concurrent loss of MLH1, PMS2 and MSH6 immunoexpression in digestive system cancers indicating a widespread dysregulation in DNA repair processes. Frontiers in oncology 21 36387226
2020 Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome. Genetics in medicine : official journal of the American College of Medical Genetics 21 31965077
2019 MSH6 immunohistochemical heterogeneity in colorectal cancer: comparative sequencing from different tumor areas. Human pathology 21 31783044
2014 High expression of the mismatch repair protein MSH6 is associated with poor patient survival in melanoma. American journal of clinical pathology 20 24926095
2010 An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC. Familial cancer 20 19851887
2009 Conformational change in MSH2-MSH6 upon binding DNA coupled to ATPase activity. Biophysical journal 20 19486659
2007 MSH2 118T>C and MSH6 159C>T promoter polymorphisms and the risk of colorectal cancer. Carcinogenesis 20 17942459
2023 Veliparib (ABT-888), a PARP inhibitor potentiates the cytotoxic activity of 5-fluorouracil by inhibiting MMR pathway through deregulation of MSH6 in colorectal cancer stem cells. Expert opinion on therapeutic targets 19 37787493
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
2019 Immunohistochemical expression of mismatch repair proteins (MSH2, MSH6, MLH1, and PMS2) in prostate cancer: correlation with grade groups (WHO 2016) and ERG and PTEN status. Virchows Archiv : an international journal of pathology 19 31209634
2002 Identification and functional characterization of the promoter region of the human MSH6 gene. Genes, chromosomes & cancer 19 11746986
2021 Classification of MSH6 Variants of Uncertain Significance Using Functional Assays. International journal of molecular sciences 18 34445333
2018 Quantitative phosphoproteomics reveals GTBP-1 regulating C.elegans lifespan at different environmental temperatures. Biochemical and biophysical research communications 18 30078680
2007 The associated contributions of p53 and the DNA mismatch repair protein Msh6 to spontaneous tumorigenesis. Carcinogenesis 18 17615258
1996 cDNA sequence, map, and expression of the murine homolog of GTBP, a DNA mismatch repair gene. Genomics 18 8812455
2014 Expression of MSH2 and MSH6 on a tissue microarray in patients with osteosarcoma. Anticancer research 17 25503122
2009 Meta-analysis of MSH6 gene mutation frequency in colorectal and endometrial cancers. Journal of toxicology and environmental health. Part A 17 19492230
2008 No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients. European journal of human genetics : EJHG 17 18301448
2007 Recently identified colon cancer predispositions: MYH and MSH6 mutations. Seminars in oncology 17 17920897

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