Affinage

MSH6

DNA mismatch repair protein Msh6 · UniProt P52701

Length
1360 aa
Mass
152.8 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MSH6 is a central component of the DNA mismatch repair (MMR) machinery, functioning as the mismatch-recognition subunit of the MutSα heterodimer with MSH2 to maintain genomic integrity by correcting single-base mismatches and small insertion/deletion loops. MutSα scans DNA by one-dimensional diffusion, discriminates mismatches through differential dissociation kinetics mediated by a conserved Phe-X-Glu motif in MSH6's mismatch-binding domain, and upon stable mismatch engagement undergoes ATP-driven conformational change to form a sliding clamp that recruits the Mlh1-Pms1 endonuclease via PCNA to activate downstream excision (PMID:7604265, PMID:10347163, PMID:17996701, PMID:20080735, PMID:24981171). Beyond canonical MMR, MSH6 directs AID targeting during somatic hypermutation and class switch recombination in B cells, mediates heteroduplex rejection during recombination with the Sgs1 helicase, promotes UV-B-induced apoptosis, and suppresses gene amplification through unequal sister chromatid exchange (PMID:15238605, PMID:16618598, PMID:15199178, PMID:14632208, PMID:11717437). Inactivation of MSH6 confers resistance to alkylating agents such as temozolomide by eliminating the futile repair cycle that mediates cytotoxicity, a clinically significant mechanism observed in glioblastoma under treatment selection (PMID:16618716, PMID:19584161).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1995 High

    Identifying MSH6 (GTBP) as the obligate partner of MSH2 for mismatch-specific DNA binding established MutSα as the functional mismatch sensor in human cells, answering how eukaryotic mismatch recognition is organized.

    Evidence Co-purification and biochemical mismatch-binding assays in human cell lines, including tumor-derived lines lacking either protein

    PMID:7604265 PMID:7604266

    Open questions at the time
    • Structural basis of the MSH2-MSH6 heterodimer was not yet resolved
    • How MutSα discriminated mismatches from homoduplex DNA was unknown
    • Downstream signaling from mismatch recognition to repair was undefined
  2. 1996 High

    Genetic epistasis in yeast delineated two parallel MutS pathways—MSH2-MSH6 for single-base mismatches and MSH2-MSH3 for larger insertion/deletion loops—resolving the question of substrate partitioning among MutS complexes.

    Evidence Mutation rate and spectrum analysis plus physical co-IP in S. cerevisiae deletion strains

    PMID:8600025 PMID:8631743

    Open questions at the time
    • Whether substrate specificity resides in the mismatch-binding domain alone was untested
    • Degree of redundancy between the two pathways in mammalian systems was unclear
  3. 1997 High

    Mouse Msh6 knockout confirmed that MSH6 is specifically required for single-nucleotide mismatch repair in vivo, validating the substrate-specificity model from yeast in a mammalian system.

    Evidence In vitro MMR assay on Msh6-null mouse cell extracts with defined mismatch substrates

    PMID:9390556

    Open questions at the time
    • How MSH6 physically contacts the mismatch at the residue level was unknown
    • Tumor spectrum of Msh6-null mice not fully characterized
  4. 1999 High

    Identification of Phe337 as the critical mismatch-contacting residue in yeast MSH6 answered how MutSα physically recognizes mismatched bases and established the Phe-X-Glu motif as the mismatch sensor.

    Evidence F337A mutagenesis with UV cross-linking, filter binding, gel retardation, and ATPase assays in vitro

    PMID:10347163

    Open questions at the time
    • Whether the Phe-X-Glu motif confers discrimination kinetically or thermodynamically was unresolved
    • Structural context of insertion into the mismatch site was not yet available
  5. 2000 High

    Discovery of the N-terminal PCNA-binding motif in MSH6 revealed how MutSα is coupled to the replication machinery, answering how mismatch repair is targeted to newly replicated DNA.

    Evidence Peptide-PCNA binding, yeast alanine-substitution mutagenesis, and human cell extract MMR inhibition assays

    PMID:11005803

    Open questions at the time
    • Whether PCNA serves as a loading platform or a processivity factor for MutSα was unclear
    • The step at which PCNA-MutSα interaction is functionally required was not precisely defined
  6. 2001 High

    Demonstrating that MSH6 loss elevates gene amplification via unequal sister chromatid exchanges expanded MSH6's role beyond point mutation repair to suppression of gross chromosomal rearrangements.

    Evidence CAD gene amplification assay in MSH6-deficient human cell lines with FISH validation

    PMID:11717437

    Open questions at the time
    • Mechanism by which MutSα suppresses unequal recombination was not determined
    • Whether this requires canonical MMR or a distinct activity was unknown
  7. 2002 High

    Biochemical reconstitution of the PCNA-MutSα ternary complex on DNA, and demonstration that mismatch binding disrupts PCNA interaction while ATP restores it, established the 'hand-off' model in which MutSα transfers from PCNA to mispairs.

    Evidence Ternary complex formation and ATP-dependent competition binding experiments with purified proteins

    PMID:12435741

    Open questions at the time
    • In vivo validation of the hand-off model was lacking
    • How ATP binding triggers conformational change enabling sliding was unresolved
  8. 2002 High

    Dominant MSH6 ATPase domain mutations that trap MutSα on mismatches revealed that ATP-driven release and sliding clamp formation are essential for downstream repair, not just mismatch recognition.

    Evidence In vitro ATPase, mispair binding, and gel-shift assays on purified dominant mutant MSH2-MSH6 complexes from yeast

    PMID:11986324

    Open questions at the time
    • Whether trapped complexes physically occlude repair factors was not shown directly
    • Structural basis of ATP-driven conformational switch was unknown
  9. 2004 High

    Showing that MSH2-MSH6 (but not Pms1) mediates heteroduplex rejection during single-strand annealing via the Sgs1 helicase established a non-canonical, repair-independent antirecombination function of MutSα.

    Evidence Yeast genetic epistasis using HO-induced DSB SSA assay with diverged and identical repeat substrates

    PMID:15199178

    Open questions at the time
    • Direct physical interaction between MutSα and Sgs1 at heteroduplex DNA was not demonstrated
    • Whether this applies to other recombination pathways was untested
  10. 2004 High

    Msh6-deficient (but not Msh3-deficient) mice showed reduced A:T mutations during somatic hypermutation and impaired class switch recombination, establishing MutSα as the specific MutS complex required for antibody diversification.

    Evidence Sequencing of Ig V and S regions from Msh6-/- and Msh3-/- mice; CSR quantification

    PMID:15238605

    Open questions at the time
    • How MutSα recognizes AID-generated lesions and channels them to error-prone repair was unknown
    • Whether MSH6's role in SHM is separable from its catalytic MMR function was unresolved
  11. 2006 High

    Msh6(TD/TD) knockin mice that lack MMR enzymatic activity but retain protein expression showed altered AID targeting, establishing that MSH6 has a scaffolding role in directing AID targeting that is separable from its catalytic repair function.

    Evidence Separation-of-function knockin mice compared to Msh6-/- and wild-type with SHM and CSR sequencing

    PMID:16618598

    Open questions at the time
    • Physical interaction between MSH6 and AID or APOBEC machinery was not demonstrated
    • Molecular details of how MSH6 protein redirects AID targeting remain unknown
  12. 2006 High

    Reconstituted dominant MSH6 mutant complexes revealed two distinct mechanisms of dominant interference—mispair occlusion and non-functional ternary complex formation with Mlh1-Pms1—clarifying how MSH6 mutations cause dominant MMR deficiency.

    Evidence ATP binding/hydrolysis, sliding clamp formation, and Mlh1-Pms1 interaction assays on multiple purified dominant mutant complexes

    PMID:16407100

    Open questions at the time
    • In vivo relevance of these two mechanisms for Lynch syndrome pathogenesis was not assessed
    • Relative prevalence of each dominant mechanism among clinical MSH6 mutations was unknown
  13. 2006 High

    Genomic analysis of temozolomide-treated gliomas revealed that somatic MSH6 inactivation is selected during therapy and confers alkylating agent resistance, answering how tumors escape alkylation damage-induced cytotoxicity.

    Evidence Matched pre/post-treatment tumor genome sequencing and mutational signature analysis

    PMID:16618716

    Open questions at the time
    • Causal directionality (selection vs. passenger) was initially correlative
    • Whether MSH6 reconstitution could restore sensitivity was untested
  14. 2007 High

    Single-molecule imaging directly visualized MutSα sliding along DNA by one-dimensional diffusion, resolving the long-debated question of how MutSα searches for mismatches on genomic DNA.

    Evidence Single-molecule fluorescence microscopy on DNA curtains

    PMID:17996701

    Open questions at the time
    • Sliding behavior on nucleosomal or chromatinized DNA was not examined
    • How sliding is modulated by ATP hydrolysis cycles in real time was unclear
  15. 2007 High

    Domain-swap chimeras replacing MSH6's mismatch-binding domain with that of MSH3 switched substrate specificity while retaining MutL interactions, definitively assigning mismatch specificity to MSH6's MBD and showing allosteric communication is conserved across MutS paralogs.

    Evidence Chimeric protein construction with mismatch repair and binding assays and MutL interaction analysis in yeast

    PMID:17573527

    Open questions at the time
    • Structural basis for allosteric communication between MBD and ATPase domain was unresolved
    • Whether human MSH6 MBD behaves identically was not tested
  16. 2008 High

    NMR structure of the MSH6 N-terminal PWWP domain revealed a non-specific DNA-binding surface, expanding understanding of how MSH6 engages DNA through regions outside the canonical mismatch-binding domain.

    Evidence NMR structure determination with DNA binding assays and HNPCC mutation mapping

    PMID:18484749

    Open questions at the time
    • Functional contribution of the PWWP domain to MMR efficiency in vivo was not quantified
    • Whether the PWWP domain cooperates with the PCNA-binding motif was unknown
  17. 2009 High

    Quantitative kinetics showed MutSα discriminates mismatches through differential dissociation rates rather than binding affinity, answering the fundamental question of how a single protein complex achieves mismatch specificity amid a vast excess of homoduplex DNA.

    Evidence Real-time stopped-flow fluorescence, ATPase assays, and functional MMR with Phe-X-Glu Glu-to-Ala mutant

    PMID:20080735

    Open questions at the time
    • In vivo validation of kinetic proofreading model was lacking
    • How chromatin context affects dissociation kinetics was unknown
  18. 2009 High

    Causal evidence that MSH6 loss drives temozolomide resistance was established by showing MSH6 knockdown increases resistance and reconstitution restores sensitivity, confirming the clinical genomic observations.

    Evidence Lentiviral shRNA knockdown, MSH6 reconstitution in null glioma cells, matched pre/post-treatment tumor sequencing

    PMID:19584161

    Open questions at the time
    • Whether other MMR genes contribute to resistance in MSH6-proficient contexts was unclear
    • Therapeutic strategies to overcome MSH6-loss-mediated resistance were not addressed
  19. 2014 High

    Demonstrating that Msh2-Msh6 localizes PCNA to mispair sites to activate the Mlh1-Pms1 endonuclease resolved how MutSα connects mismatch recognition to the downstream incision step, particularly in the Exo1-independent MMR pathway.

    Evidence Genetic screen for PCNA mutations specific to Exo1-independent MMR, biochemical PCNA-MutSα and PCNA-MutLα interaction assays, MutLα foci quantification in yeast

    PMID:24981171

    Open questions at the time
    • Whether this mechanism operates identically in human cells was not confirmed
    • Structural basis of the PCNA-MutSα-MutLα ternary assembly at mispairs was unresolved
  20. 2022 Medium

    Identification of S6K1-mediated phosphorylation of MSH6 at Ser309 as an enhancer of MMR activity linked nutrient/growth factor signaling to mismatch repair regulation.

    Evidence In vitro kinase assay, phospho-site identification, S6K1 knockdown/overexpression with functional MMR assays

    PMID:36189922

    Open questions at the time
    • In vivo significance of Ser309 phosphorylation under physiological conditions was not established
    • Whether this phosphorylation affects MutSα complex formation or sliding clamp dynamics is unknown
    • Single-lab finding awaiting independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how MSH6's scaffolding role in AID targeting is mechanistically achieved, how chromatin context modulates MutSα scanning and mismatch discrimination in vivo, and what structural basis underlies the allosteric coupling between MSH6's mismatch-binding domain and its ATPase domain during sliding clamp formation.
  • No direct AID-MSH6 physical interaction demonstrated
  • No cryo-EM or crystal structure of the full-length human MutSα sliding clamp on mismatch DNA
  • In vivo single-molecule studies of MutSα on chromatin are lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140097 catalytic activity, acting on DNA 4 GO:0140657 ATP-dependent activity 4
Localization
GO:0005694 chromosome 3 GO:0005634 nucleus 2
Pathway
R-HSA-73894 DNA Repair 11 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2
Partners
MLH1MSH2PCNAPMS1SGS1
Complex memberships
MutSα (MSH2-MSH6)

Evidence

Reading pass · 29 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, as loss of either abolishes mismatch-binding activity in human cells. Protein co-purification, biochemical mismatch-binding assay, analysis of tumor-derived cell lines lacking either protein Science High 7604265 7604266
1996 In S. cerevisiae, MSH6 partners with MSH2 to form one of two MSH2-dependent mismatch repair pathways: the MSH2-MSH6 pathway repairs single-base mispairs and single-nucleotide insertion/deletion mismatches, while MSH2-MSH3 preferentially repairs larger insertion/deletion loops; the two pathways are partially redundant. Mutation rate measurement, mutation spectrum analysis, physical interaction studies (co-IP/pulldown of MSH2 with MSH3 and MSH6) in S. cerevisiae mutant strains Genes & development High 8600025 8631743
1995 GTBP/MSH6 deficiency in human tumor cells causes microsatellite instability preferentially at mononucleotide tracts, distinct from the broader instability (mononucleotide and dinucleotide repeats) seen in MSH2/MLH1-deficient cells, indicating MSH6 has a specific substrate preference. Microsatellite instability analysis of GTBP-deficient hypermutable cell lines; gene localization and sequencing Science High 7604266
1997 Mouse Msh6 knockout cells are specifically defective for repair of single-nucleotide mismatches but retain repair of 1-, 2-, and 4-nucleotide insertion/deletion mismatches, establishing MSH6's substrate specificity in vivo. Gene targeting (Msh6 null mouse), cell extracts assayed for mismatch repair activity in vitro Cell High 9390556
2000 MSH6 and MSH3 (but not MSH2) contain N-terminal PCNA-binding motifs; MSH6 peptides containing this motif bind PCNA, the intact MSH2-MSH6 complex binds PCNA, and alanine substitutions in the PCNA-binding motif of MSH6 elevate mutation rates in yeast and inhibit mismatch repair in human cell extracts at a step preceding DNA resynthesis. Peptide-PCNA binding assay, yeast mutagenesis with alanine-substitution strains, human cell extract mismatch repair inhibition assay The Journal of biological chemistry High 11005803
2002 PCNA and MSH2-MSH6 form a stable ternary complex on homoduplex DNA; MSH2-MSH6 binding to a G/T mismatch disrupts its interaction with PCNA, and addition of ATP restores PCNA binding, supporting a model in which MSH2-MSH6 is transferred from PCNA to mispaired bases. Biochemical ternary complex assay, competition binding experiments with ATP The Journal of biological chemistry High 12435741
1999 A phenylalanine-to-alanine substitution (F337A) in the mismatch-recognition domain of yeast MSH6 disrupts stable mismatch DNA binding by the MSH2-MSH6 complex without affecting MSH2 interaction, identifying this residue as critical for mismatch recognition. UV cross-linking, filter binding, gel retardation assays, ATPase analysis, yeast genetics The Journal of biological chemistry High 10347163
2002 Dominant msh6 mutations (G1067D, G1142D, S1036P, H1096A) in yeast cause increased mispair binding and decreased dissociation from mispairs in the presence of ATP, inhibiting ATP-induced release of MSH2-MSH6 from mismatches; this reveals that ATP-driven conformational change is required for normal mismatch repair. In vitro ATPase assays, mispair binding assays with ATP, gel-shift analysis of dominant mutant MSH2-MSH6 complexes The Journal of biological chemistry High 11986324
2006 Dominant MSH6 mutations act by two mechanisms: (1) mutant MSH2-MSH6 binds mispairs but is defective for ATP-induced sliding clamp formation and Mlh1-Pms1 complex assembly, occluding mispairs from other repair pathways; (2) alternatively, mutant complex assembles ternary complexes with Mlh1-Pms1 that prevent Mlh1-Pms1 from acting in MMR. ATP binding, ATP hydrolysis, mispair binding, sliding clamp formation, and Mlh1-Pms1 interaction assays on purified dominant mutant complexes Proceedings of the National Academy of Sciences of the United States of America High 16407100
2007 The MSH2-MSH6 complex slides along DNA via one-dimensional diffusion to scan for mismatches, as demonstrated by single-molecule optical microscopy on undamaged DNA. Single-molecule fluorescence optical microscopy (single-molecule DNA curtains assay) Molecular cell High 17996701
2009 Msh2-Msh6 binds all DNA sites at similarly fast on-rates (~10^7 M−1s−1) but discriminates mismatches through differential dissociation rates (e.g., ~90-fold slower release from G:T vs. 2-Aminopurine:T); long-lived mismatch complexes trigger ATP-bound clamp formation and initiate MMR, while short-lived non-mismatch complexes do not. Real-time kinetic binding assays, stopped-flow fluorescence, ATPase assay, functional MMR assay with Glu-to-Ala mutation in Phe-X-Glu motif Proceedings of the National Academy of Sciences of the United States of America High 20080735
2004 Msh6-deficient mice show reduced A:T mutations during somatic hypermutation and reduced class switch recombination, while Msh3-deficient mice are normal, establishing that the Msh2-Msh6 heterodimer (not Msh2-Msh3) is required for generating A:T substitutions and for class switch recombination in B cells. Sequencing of immunoglobulin V and S regions from Msh3-/- and Msh6-/- mice; class switch recombination assay The Journal of experimental medicine High 15238605
2006 Msh6 protein influences AID targeting in vivo during somatic hypermutation: Msh6(TD/TD) knockin mice lacking MMR enzymatic activity still show altered AID targeting to non-WRC motifs in phase one of SHM, suggesting Msh6 plays a scaffolding/structural role in directing AID targeting independently of its catalytic MMR function. Point-mutant Msh6 knockin (Msh6TD/TD) mice compared to Msh6-/- and wild-type; SHM and CSR sequencing Immunity High 16618598
2002 MSH2 and MSH6 proteins forming the MutSα complex are phosphorylated in vivo by protein kinase C and casein kinase II; loss of phosphorylation (via kinase inhibition or phosphatase treatment) reduces mismatch-binding activity of MutSα and prevents methylation-induced nuclear translocation of the repair complex. In vitro kinase assay, phosphate depletion, kinase inhibitors, phosphatase treatment, mismatch-binding assay, nuclear translocation assay Nucleic acids research Medium 11972333
2008 Human MSH6 contains a PWWP domain in its N-terminal region that binds double-stranded DNA without mismatch specificity; the S144I HNPCC-associated mutation is located in the DNA-binding surface of this PWWP domain but does not abolish DNA binding in vitro. NMR structure determination of PWWP domain, DNA binding assays, mutant stability and binding analysis Biochemistry High 18484749
2007 The N-terminal region (NTR) of yeast Msh6 (residues 228–299) contains a positively charged stretch that binds duplex DNA in a mismatch-independent manner; deletion or charge-reversal mutations in this region reduce DNA binding and elevate spontaneous mutation rates and sensitivity to alkylating agent MNNG in vivo. Partial proteolysis, DNA affinity chromatography, mass spectrometry, in vitro DNA binding, yeast mutant phenotyping Nucleic acids research High 17567610
2014 PCNA activates the Mlh1-Pms1 endonuclease in an Exo1-independent MMR pathway; Msh2-Msh6 localizes PCNA to repair sites after mispair recognition to enable Mlh1-Pms1 endonuclease activation, as demonstrated by PCNA mutations that selectively disrupt trimerization/Msh2-Msh6 binding or Mlh1-Pms1 endonuclease activation. Genetic screen for pol30 (PCNA) mutations specific to Exo1-independent MMR, biochemical analysis of PCNA-Msh2-Msh6 and PCNA-Mlh1-Pms1 interactions, Mlh1-Pms1 foci quantification Molecular cell High 24981171
2004 In yeast, MSH2 domain I (mismatch recognition domain) is required for MSH2-MSH3-mediated MMR but is dispensable for MSH2-MSH6-mediated MMR, revealing distinct structural requirements for mismatch binding between the two MutS complexes. Yeast genetics (msh2Δ1 separation-of-function mutant), in vitro mismatch binding assays, recombination assays Journal of molecular biology High 17157869
2007 A chimeric yeast protein in which the mispair-binding domain (MBD) of Msh6 is replaced by that of Msh3 acquires Msh3-like mispair-binding specificity while retaining Msh6-like interactions with MutL homologs, demonstrating that the MBD determines mispair specificity and that allosteric communication between MBD and ATPase domain is conserved. Chimeric protein construction, mismatch repair assays, mispair binding assays, genetic interaction analysis with MutL homologs Proceedings of the National Academy of Sciences of the United States of America High 17573527
2012 Human MSH2(G674A)-MSH6 and MSH2-MSH6(T1219D) complexes fail to support MMR in vitro despite retaining mismatch recognition; MSH6(T1219D) fails to couple nucleotide binding to mismatch recognition, while MSH2(G674A) has a partial defect in nucleotide binding; both mutant complexes remain trapped at mismatches and inhibit MMR in a dominant manner. Purified mutant MutSα proteins, in vitro MMR assay, DNA binding kinetics, ATPase assay, excision step analysis The Journal of biological chemistry High 22277660
2003 Msh6-deficient primary mouse fibroblasts are less sensitive to UV-B cytotoxicity and undergo significantly less UV-B-induced apoptosis than wild-type cells, establishing that Msh6 promotes apoptosis in response to UV-B damage independently of p53. Msh6-/- primary mouse embryonic fibroblasts, UV-B irradiation, apoptosis assays, cytotoxicity assays, protein level analysis The Journal of investigative dermatology High 14632208
2001 Loss of MSH6 (or MLH1) in human cells elevates the rate of CAD gene amplification 50–100-fold above mismatch repair-proficient controls, through unequal sister chromatid exchanges and translocations, implicating MutSα in the suppression of gene amplification. CAD gene amplification assay in MMR-deficient human cell lines, fluorescence in situ hybridization (FISH) Proceedings of the National Academy of Sciences of the United States of America High 11717437
2022 S6K1 phosphorylates MSH6 at serine 309, enhancing mismatch repair (MMR); this phosphorylation event is part of a coordinated DNA damage response in which S6K1 also phosphorylates Cdk1 at serine 39 to enable homologous recombination. In vitro kinase assay, phospho-specific site identification, S6K1 knockdown/overexpression, MMR and HR functional assays eLife Medium 36189922
2023 MSH6 undergoes lysine crotonylation (at K544) in fetal oocytes; this modification promotes association with Ku70 to favor homologous recombination over non-homologous end joining during meiosis; DBP exposure reduces Kcr of MSH6 and impairs HR. Targeted Msh6 disruption in fetal ovaries, K544cr site-directed mutagenesis, Co-IP of MSH6 with Ku70, HR vs. NHEJ pathway assays, meiotic phenotype analysis Journal of hazardous materials Medium 37167869
2004 In yeast, heteroduplex rejection during single-strand annealing requires MSH2 and MSH6 (but not PMS1), and the SGS1 helicase; heteroduplex DNA is likely unwound rather than degraded, suggesting MSH2-MSH6 recruits Sgs1 to unwind mismatched recombination intermediates. Yeast genetic deletion strains, HO endonuclease-induced DSB SSA assay, competition assay between diverged and identical repeat substrates Proceedings of the National Academy of Sciences of the United States of America High 15199178
2006 Inactivating somatic MSH6 mutations confer resistance to the alkylating agent temozolomide in gliomas in vivo and in vitro, as demonstrated by sequencing of post-treatment gliomas and large-scale mutational signature analysis showing alkylation-type hypermutation only in MSH6-mutant tumors. Tumor genome sequencing, mutational signature analysis in matched pre/post-treatment gliomas Cancer research High 16618716
2009 MSH6 mutations arise in glioblastomas specifically during temozolomide therapy (absent in pre-treatment samples) and are causally associated with temozolomide resistance: MSH6 knockdown increases resistance, and MSH6 reconstitution in MSH6-null glioma cells restores temozolomide cytotoxicity. Matched pre/post-treatment tumor sequencing, in vitro temozolomide-resistant clone selection with MSH6 sequencing, lentiviral shRNA knockdown, MSH6 reconstitution in null cells Clinical cancer research High 19584161
2002 The MSH6 gene is transcribed from a classical housekeeping promoter; MSH6 transcription is upregulated during late G1 phase of the cell cycle even though protein levels remain essentially constant; the promoter does not respond to ionizing radiation or heavy metals despite containing AP1, NF-κB, and MTF-1 binding sites. Promoter isolation, reporter gene assays, cell cycle synchronization experiments, RT-PCR Genes, chromosomes & cancer Medium 11746986
2018 MSH6 knockdown in pituitary adenoma cells (AtT-20ins) decreases ATR expression, promotes cell proliferation and cell-cycle progression, and reduces PD-L1 expression; this links MSH6 to direct regulation of tumor cell growth via the ATR-Chk1 pathway. siRNA knockdown of MSH6 in AtT-20ins cells and primary culture, real-time PCR for ATR/Chk1 pathway genes, cell proliferation assays The 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 834 21642682
1996 Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair. Genes & development 501 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.) 483 7604265
1997 Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred. Cancer research 373 9307272
2006 A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer research 361 16618716
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 321 19584161
1997 Mutation in the mismatch repair gene Msh6 causes cancer susceptibility. Cell 313 9390556
2009 Risks of Lynch syndrome cancers for MSH6 mutation carriers. Journal of the National Cancer Institute 294 20028993
2002 Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. American journal of human genetics 220 11709755
2014 Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer. Nature communications 214 25255306
2007 Dynamic basis for one-dimensional DNA scanning by the mismatch repair complex Msh2-Msh6. Molecular cell 182 17996701
2004 Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 182 15483016
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
2004 Heteroduplex rejection during single-strand annealing requires Sgs1 helicase and mismatch repair proteins Msh2 and Msh6 but not Pms1. Proceedings of the National Academy of Sciences of the United States of America 174 15199178
1996 Requirement of the yeast MSH3 and MSH6 genes for MSH2-dependent genomic stability. The Journal of biological chemistry 170 8631743
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
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
2001 Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree. Journal of medical genetics 122 11333868
2010 Neoadjuvant therapy induces loss of MSH6 expression in colorectal carcinoma. The American journal of surgical pathology 118 21107085
2011 Frequent promoter hypermethylation of BRCA2, CDH13, MSH6, PAX5, PAX6 and WT1 in ductal carcinoma in situ and invasive breast cancer. The Journal of pathology 116 21710692
2002 MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer. Cancer research 111 11830542
2010 Immunohistochemistry for PMS2 and MSH6 alone can replace a four antibody panel for mismatch repair deficiency screening in colorectal adenocarcinoma. Pathology 107 20632815
2006 Somatic hypermutation and class switch recombination in Msh6(-/-)Ung(-/-) double-knockout mice. Journal of immunology (Baltimore, Md. : 1950) 96 17015724
2014 PCNA and Msh2-Msh6 activate an Mlh1-Pms1 endonuclease pathway required for Exo1-independent mismatch repair. Molecular cell 89 24981171
2003 Altered expression of MLH1, MSH2, and MSH6 in predisposition to hereditary nonpolyposis colorectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 85 14512394
2002 Transfer of the MSH2.MSH6 complex from proliferating cell nuclear antigen to mispaired bases in DNA. The Journal of biological chemistry 84 12435741
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 80 10507723
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
2009 Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management. Hereditary cancer in clinical practice 64 20028567
2002 Phosphorylation of mismatch repair proteins MSH2 and MSH6 affecting MutSalpha mismatch-binding activity. Nucleic acids research 62 11972333
2000 EXO1 and MSH6 are high-copy suppressors of conditional mutations in the MSH2 mismatch repair gene of Saccharomyces cerevisiae. Genetics 62 10835383
2003 Dissimilar mispair-recognition spectra of Arabidopsis DNA-mismatch-repair proteins MSH2*MSH6 (MutSalpha) and MSH2*MSH7 (MutSgamma). Nucleic acids research 61 14530450
2002 Functional analysis of MSH6 mutations linked to kindreds with putative hereditary non-polyposis colorectal cancer syndrome. Human molecular genetics 60 12019211
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
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2011 Regulation of plant MSH2 and MSH6 genes in the UV-B-induced DNA damage response. Journal of experimental botany 42 21307385
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2013 ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma. Clinical lung cancer 38 23810210
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2020 MSH6/2 and PD-L1 Expressions Are Associated with Tumor Growth and Invasiveness in Silent Pituitary Adenoma Subtypes. International journal of molecular sciences 28 32325698
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