MSH6

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MutS homolog 6 (E. coli)
Protein MSH6 PDB 2gfu.png
PDB rendering based on 2gfu.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols MSH6 ; GTBP; HNPCC5; HSAP
External IDs OMIM600678 MGI1343961 HomoloGene149 GeneCards: MSH6 Gene
RNA expression pattern
PBB GE MSH6 202911 at tn.png
PBB GE MSH6 211450 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2956 17688
Ensembl ENSG00000116062 ENSMUSG00000005370
UniProt P52701 P54276
RefSeq (mRNA) NM_000179 NM_010830
RefSeq (protein) NP_000170 NP_034960
Location (UCSC) Chr 2:
48.01 – 48.03 Mb
Chr 17:
87.98 – 87.99 Mb
PubMed search [1] [2]

MSH6 or mutS homolog 6 is a gene that codes for DNA mismatch repair protein Msh6 in the budding yeast Saccharomyces cerevisiae. It is the homologue of the human "G/T binding protein," (GTBP) also called p160 or hMSH6 (human MSH6). The MSH6 protein is a member of the Mutator S (MutS) family of proteins that are involved in DNA damage repair.

Defects in hMSH6 are associated with atypical hereditary nonpolyposis colorectal cancer not fulfilling the Amsterdam criteria for HNPCC. hMSH6 mutations have also been linked to endometrial cancer and the development of endometrial carcinomas.

Discovery[edit]

MSH6 was first identified in the budding yeast S. cerevisiae because of its homology to MSH2. The identification of the human GTBP gene and subsequent amino acid sequence availability showed that yeast MSH6 and human GTBP were more related to each other than any other MutS homolog, with a 26.6% amino acid identity. [1] Thus, GTBP took on the name human MSH6, or hMSH6.

Structure[edit]

In the human genome, hMSH6 is located on chromosome 2. It contains the Walker-A/B adenine nucleotide binding motif, which is the most highly conserved sequence found in all MutS homologs.[2] As with other MutS homologs, hMSH6 has an intrinsic ATPase activity. It functions exclusively when bound to hMSH2 as a heterodimer, although hMSH2 itself can function as a homomultimer or as a heterodimer with hMSH3. [3]

Function[edit]

Importance of mismatch repair[edit]

Mismatches commonly occur as a result of DNA replication errors, genetic recombination, or other chemical and physical factors. [4] Recognizing those mismatches and repairing them is extremely important for cells, because failure to do so results in microsatellite instability, an elevated spontaneous mutation rate (mutator phenotype), and susceptibility to HNPCC. [5][2] hMSH6 combines with hMSH2 to form the active protein complex, hMutS alpha, also called hMSH2-hMSH6.

Mismatch recognition[edit]

Mismatch recognition by this complex is regulated by the ADP to ATP transformation, which provides evidence that hMutS alpha complex functions as a molecular switch. [6]In normal DNA, adenine (A) bonds with thymine (T) and cytosine (C) bonds with guanine (G). Sometimes there will be a mismatch where T will bind with G, which is called a G/T mismatch. When a G/T mismatch is recognized, hMutS alpha complex binds and exchanges ADP for ATP.[5] The ADP-->ATP exchange causes a conformational change to convert hMutS alpha into a sliding clamp that can diffuse along the DNA backbone.[5] The ATP induces a release of the complex from the DNA and allows the hMutS alpha to dissociate along the DNA like a sliding clamp. This transformation helps trigger downstream events to repair the damaged DNA.[5]

Cancer Research[edit]

Mutations in hMSH6[edit]

Although mutations in hMSH2 cause a strong general mutator phenotype, mutations in hMSH6 cause only a modest mutator phenotype.[1] At the gene level, the mutations were found to cause primarily single-base substitution mutations, which suggests that the role of hMSH6 is primarily for correcting single-base substitution mutations and to a lesser extent single base insertion/deletion mutations. [1]

Mutations in the hMSH6 gene cause the protein to be nonfunctional or only partially active, thus reducing its ability to repair mistakes in DNA. The loss of MSH6 function results in instability at mononucleotide repeats. [1] HNPCC is most commonly caused by mutations in hMSH2 and hMLH1, but mutations in hMSH6 are linked to an atypical form of HNPCC. [7] The penetrance of colorectal cancer seems to be lower in these mutations, meaning that a low proportion of hMSH6 mutation carriers present with the disease. Endometrial cancer, on the other hand, seems to be a more important clinical manifestation for female mutation carriers. The onset of endometrial cancer and also colon cancer in families with hMSH6 mutations is about 50 years. This is delayed compared to the age 44 onset of hMSH2-related tumors. [7]

Interactions[edit]

MSH6 has been shown to interact with MSH2,[8][9][10][11][12] PCNA[13][14][15] and BRCA1.[8][16]

See also[edit]

References[edit]

  1. ^ a b c d Marsischky GT, et al. (1996) Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair. ‘’Genes Dev.’’ 10(4):407-20. doi: 10.1101/gad.10.4.407. PMID:8600025
  2. ^ a b Fishel R, Kolodner RD. (1995). Identification of mismatch repair genes and their role in the development of cancer. Current Opinion in Genetics & Development. 5:382-95. doi: 10.1016/0959-437X(95)80055-7. PMID 7549435.
  3. ^ Acharya S, et al. (1996) hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. ‘’PNAS.’’ 93(24):13629-34. doi: 10.1073/pnas.93.24.13629. PMID 8942985.
  4. ^ Friedberg EC, Walker GC, Siede W. (1995). DNA repair and mutagenesis. American Society for Microbiology, Washington DC.
  5. ^ a b c d Gradia S, et al. (1999). hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA. ‘’Molecular Cell.’’ 3(2):255-61. doi=10.1016/S1097-2765(00)80316-0. PMID 10078208
  6. ^ Gradia S, Acharya S, Fishel R. (1997) The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch. ‘’Cell.’’ 91:995-1005. doi: 10.1016/S0092-8674(00)80490-0. PMID 9428522.
  7. ^ a b Wagner, A; et al. (2001). Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree. ‘’J. Med. Genet.’’ 38(5):318–22. doi: 10.1136/jmg.38.5.318. PMID 11333868.
  8. ^ a b Wang, Y; Cortez D, Yazdi P, Neff N, Elledge S J, Qin J (April 2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. (UNITED STATES) 14 (8): 927–39. ISSN 0890-9369. PMC 316544. PMID 10783165. 
  9. ^ Wang, Yi; Qin June (December 2003). "MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation". Proc. Natl. Acad. Sci. U.S.A. (United States) 100 (26): 15387–92. doi:10.1073/pnas.2536810100. ISSN 0027-8424. PMC 307577. PMID 14657349. 
  10. ^ Guerrette, S; Wilson T, Gradia S, Fishel R (November 1998). "Interactions of human hMSH2 with hMSH3 and hMSH2 with hMSH6: examination of mutations found in hereditary nonpolyposis colorectal cancer". Mol. Cell. Biol. (UNITED STATES) 18 (11): 6616–23. ISSN 0270-7306. PMC 109246. PMID 9774676. 
  11. ^ Bocker, T; Barusevicius A, Snowden T, Rasio D, Guerrette S, Robbins D, Schmidt C, Burczak J, Croce C M, Copeland T, Kovatich A J, Fishel R (February 1999). "hMSH5: a human MutS homologue that forms a novel heterodimer with hMSH4 and is expressed during spermatogenesis". Cancer Res. (UNITED STATES) 59 (4): 816–22. ISSN 0008-5472. PMID 10029069. 
  12. ^ Acharya, S; Wilson T, Gradia S, Kane M F, Guerrette S, Marsischky G T, Kolodner R, Fishel R (November 1996). "hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 93 (24): 13629–34. doi:10.1073/pnas.93.24.13629. ISSN 0027-8424. PMC 19374. PMID 8942985. 
  13. ^ Kleczkowska, H E; Marra G, Lettieri T, Jiricny J (March 2001). "hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci". Genes Dev. (United States) 15 (6): 724–36. doi:10.1101/gad.191201. ISSN 0890-9369. PMC 312660. PMID 11274057. 
  14. ^ Clark, A B; Valle F, Drotschmann K, Gary R K, Kunkel T A (November 2000). "Functional interaction of proliferating cell nuclear antigen with MSH2-MSH6 and MSH2-MSH3 complexes". J. Biol. Chem. (UNITED STATES) 275 (47): 36498–501. doi:10.1074/jbc.C000513200. ISSN 0021-9258. PMID 11005803. 
  15. ^ Ohta, Satoshi; Shiomi Yasushi, Sugimoto Katsunori, Obuse Chikashi, Tsurimoto Toshiki (October 2002). "A proteomics approach to identify proliferating cell nuclear antigen (PCNA)-binding proteins in human cell lysates. Identification of the human CHL12/RFCs2-5 complex as a novel PCNA-binding protein". J. Biol. Chem. (United States) 277 (43): 40362–7. doi:10.1074/jbc.M206194200. ISSN 0021-9258. PMID 12171929. 
  16. ^ Wang, Q; Zhang H, Guerrette S, Chen J, Mazurek A, Wilson T, Slupianek A, Skorski T, Fishel R, Greene M I (August 2001). "Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1". Oncogene (England) 20 (34): 4640–9. doi:10.1038/sj.onc.1204625. ISSN 0950-9232. PMID 11498787. 

External links[edit]

Further reading[edit]