MGP Database

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MGP001361

UniProt Annotations

Entry Information
Gene NamemutS homolog 6
Protein EntryMSH6_HUMAN
UniProt IDP52701
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=4; Name=GTBP-N; IsoId=P52701-1; Sequence=Displayed; Name=GTBP-alt; IsoId=P52701-2; Sequence=VSP_003291, VSP_003292; Name=3; IsoId=P52701-3; Sequence=VSP_054419; Note=No experimental confirmation available.; Name=4; IsoId=P52701-4; Sequence=VSP_055020; Note=No experimental confirmation available.;
DiseaseEndometrial cancer (ENDMC) [MIM:608089]: A malignancy of endometrium, the mucous lining of the uterus. Most endometrial cancers are adenocarcinomas, cancers that begin in cells that make and release mucus and other fluids. {ECO:0000269|PubMed:11153917, ECO:0000269|PubMed:14961575}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
DiseaseHereditary non-polyposis colorectal cancer 5 (HNPCC5) [MIM:614350]: An autosomal dominant disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early-onset colorectal carcinoma (CRC) and extra-colonic tumors of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world. Clinically, HNPCC is often divided into two subgroups. Type I is characterized by hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II is characterized by increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected. {ECO:0000269|PubMed:10480359, ECO:0000269|PubMed:10521294, ECO:0000269|PubMed:11586295, ECO:0000269|PubMed:12658575, ECO:0000269|PubMed:14974087, ECO:0000269|PubMed:15365995, ECO:0000269|PubMed:9354786}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseMismatch repair cancer syndrome (MMRCS) [MIM:276300]: An autosomal recessive, rare, childhood cancer predisposition syndrome encompassing a broad tumor spectrum. This includes hematological malignancies, central nervous system tumors, Lynch syndrome-associated malignancies such as colorectal tumors as well as multiple intestinal polyps, embryonic tumors and rhabdomyosarcoma. Multiple cafe-au-lait macules, a feature reminiscent of neurofibromatosis type 1, are often found as first manifestation of the underlying cancer. Areas of skin hypopigmentation have also been reported in MMRCS patients. {ECO:0000269|PubMed:17557300}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DomainThe PWWP domain specifically recognizes and binds trimethylated 'Lys-36' of histone H3 (H3K36me3). {ECO:0000269|PubMed:23622243}.
FunctionComponent of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MSH2 to form MutS alpha, which binds to DNA mismatches thereby initiating DNA repair. When bound, MutS alpha bends the DNA helix and shields approximately 20 base pairs, and recognizes single base mismatches and 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, and resynthesis. ATP binding and 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. Recruited on chromatin in G1 and early S phase via its PWWP domain that specifically binds trimethylated 'Lys-36' of histone H3 (H3K36me3): early recruitment to chromatin to be replicated allowing a quick identification of mismatch repair to initiate the DNA mismatch repair reaction. {ECO:0000269|PubMed:10078208, ECO:0000269|PubMed:10660545, ECO:0000269|PubMed:15064730, ECO:0000269|PubMed:23622243, ECO:0000269|PubMed:9564049, ECO:0000269|PubMed:9822679, ECO:0000269|PubMed:9822680}.
InteractionP43246:MSH2; NbExp=5; IntAct=EBI-395529, EBI-355888;
PtmPhosphorylated by PRKCZ, which may prevent MutS alpha degradation by the ubiquitin-proteasome pathway. {ECO:0000269|PubMed:15808853, ECO:0000269|PubMed:16964243, ECO:0000269|PubMed:17081983, ECO:0000269|PubMed:18669648, ECO:0000269|PubMed:18691976, ECO:0000269|PubMed:20068231, ECO:0000269|PubMed:21406692}.
PtmThe N-terminus is blocked.
SimilarityBelongs to the DNA mismatch repair MutS family. {ECO:0000305}.
SimilarityContains 1 PWWP domain. {ECO:0000255|PROSITE- ProRule:PRU00162}.
Subcellular LocationNucleus {ECO:0000269|PubMed:23622243}. Chromosome {ECO:0000269|PubMed:23622243}. Note=Associates with H3K36me3 via its PWWP domain.
SubunitHeterodimer 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), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with ATR.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/MSH6ID344ch2p16.html";
Web ResourceName=Hereditary non-polyposis colorectal cancer db; URL="http://www.nfdht.nl/";
Web ResourceName=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/msh6/";
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