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DNA mismatch repair protein Msh6; hMSH6; mutS-alpha 160 kD subunit; p160; G/T mismatch-binding protein; GTMBP; GTBP (MSH6 GTBP)

Function: - component of the post-replicative DNA mismatch repair system (MMR) - recognizes base-pair mismatches, particularly G/T - heterodimerizes with MSH2 to form mutS alpha, which binds to DNA mismatches thereby initiating DNA repair - when bound, mutS alpha bends the DNA helix & shields approximately 20 base pairs, & recognizes single base mismatches & dinucleotide insertion-deletion loops (IDL) in the DNA - after mismatch binding, forms a ternary complex with the mutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, & resynthesis - ATP binding & hydrolysis play a pivotal role in mismatch repair functions - the ATPase activity associated with mutS alpha regulates binding similar to a molecular switch: mismatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts mutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone - this transition is crucial for mismatch repair - mutS alpha may also play a role in DNA homologous recombination repair - the N-terminus is blocked - phosphorylated upon DNA damage, probably by ATM or ATR - phosphorylated by PRKCZ, which may prevent mutS alpha degradation by the ubiquitin-proteasome pathway - heterodimer consisting of MSH2-MSH6 (mutS alpha) - forms a ternary complex with mutL alpha (MLH1-PMS1) - interacts with EXO1 - part of the BRCA1-associated genome surveillance complex (BASC) - this association could be a dynamic process changing throughout the cell cycle & within subnuclear domains. - interacts with ATR Structure: - belongs to the DNA mismatch repair mutS family - contains 1 PWWP domain Compartment: nucleus Alternative splicing: - named isoforms=2 - GTBP-N, TBP-alt Pathology: - defects in MSH6 are the cause of a) hereditary non-polyposis colorectal cancer type 5 b) susceptibility to endometrial cancer [MIM:608089]

Interactions

molecular events

General

helicase (DNA unwinding protein, DNA untwisting protein) mutS family protein

Properties

SIZE: entity length = 1360 aa MW = 153 kD MOTIF: Ser phosphorylation site {S14} alanine-rich region {34-37} MOTIF: alanine residue (SEVERAL) Ser phosphorylation site {S41} Ser phosphorylation site {S43} Ser phosphorylation site {S79} Ser phosphorylation site {S91} PWWP domain {92-154} MOTIF: Ser phosphorylation site {S137} Thr phosphorylation site {T139} Ser phosphorylation site {S200} glutamate-rich region {201-209} MOTIF: glutamate residue (SEVERAL) Ser phosphorylation site {S219} Ser phosphorylation site {S227} Ser phosphorylation site {S252} Ser phosphorylation site {S254} Ser phosphorylation site {S256} Ser phosphorylation site {S261} Ser phosphorylation site {S309} Ser phosphorylation site {S348} Ser phosphorylation site {S830} Thr phosphorylation site {T924} binding site EFFECTOR-BOUND: DNA mismatch repair protein Msh2 glutamate-rich region {1118-1123} MOTIF: glutamate residue (SEVERAL) ATP-binding site NAME: ATP-binding site SITE: 1134-1141

Database Correlations

OMIM correlations MORBIDMAP 600678 UniProt P52701 PFAM correlations Entrez Gene 2956 Kegg hsa:2956

References

  1. UniProt :accession P52701
  2. Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/MSH6ID344ch2p16.html
  3. GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/MSH6
  4. Hereditary non-polyposis colorectal cancer db http://www.nfdht.nl/
  5. NIEHS-SNPs http://egp.gs.washington.edu/data/msh6/
  6. Palombo F, Hughes M, Jiricny J, Truong O, Hsuan J. Mismatch repair and cancer. Nature. 1994 Feb 3;367(6462):417. PMID: 8107798
  7. Kolodner RD. Mismatch repair: mechanisms and relationship to cancer susceptibility. Trends Biochem Sci. 1995 Oct;20(10):397-401. Review. PMID: 8533151
  8. Karran P. Appropriate partners make good matches. Science. 1995 Jun 30;268(5219):1857-8. Review. PMID: 7604258

Component-of

BRCA1-associated genome surveillance complex (BASC)