Human Gene MSH6 (ENST00000234420.11_10) from GENCODE V47lift37
Description: Component 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. (from UniProt P52701) Gencode Transcript: ENST00000234420.11_10 Gencode Gene: ENSG00000116062.19_18 Transcript (Including UTRs) Position: hg19 chr2:48,010,284-48,034,092 Size: 23,809 Total Exon Count: 10 Strand: + Coding Region Position: hg19 chr2:48,010,373-48,033,999 Size: 23,627 Coding Exon Count: 10
ID:MSH6_HUMAN DESCRIPTION: RecName: Full=DNA mismatch repair protein Msh6; Short=hMSH6; AltName: Full=G/T mismatch-binding protein; Short=GTBP; Short=GTMBP; AltName: Full=MutS-alpha 160 kDa subunit; Short=p160; FUNCTION: Component 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. SUBUNIT: 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), 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. INTERACTION: P43246:MSH2; NbExp=4; IntAct=EBI-395529, EBI-355888; SUBCELLULAR LOCATION: Nucleus. PTM: The N-terminus is blocked. PTM: Phosphorylated upon DNA damage, probably by ATM or ATR. PTM: Phosphorylated by PRKCZ, which may prevent MutS alpha degradation by the ubiquitin-proteasome pathway. DISEASE: Defects in MSH6 are the cause of hereditary non-polyposis colorectal cancer type 5 (HNPCC5) [MIM:614350]. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPCC phenotype (also called Lynch syndrome). Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly inherited disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early onset colorectal carcinoma (CRC) and extra-colonic cancers 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. Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Clinically, HNPCC is often divided into two subgroups. Type I: hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II: patients have an 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. MSH6 mutations appear to be associated with atypical HNPCC and in particular with development of endometrial carcinoma or atypical endometrial hyperplasia, the presumed precursor of endometrial cancer. Defects in MSH6 are also found in familial colorectal cancers (suspected or incomplete HNPCC) that do not fulfill the Amsterdam criteria for HNPCC. DISEASE: Defects in MSH6 are a cause of susceptibility to endometrial cancer (ENDMC) [MIM:608089]. DISEASE: Defects in MSH6 are a cause of mismatch repair cancer syndrome (MMRCS) [MIM:276300]; also known as Turcot syndrome or brain tumor-polyposis syndrome 1 (BTPS1). MMRCS is an autosomal dominant disorder characterized by malignant tumors of the brain associated with multiple colorectal adenomas. Skin features include sebaceous cysts, hyperpigmented and cafe au lait spots. SIMILARITY: Belongs to the DNA mismatch repair MutS family. SIMILARITY: Contains 1 PWWP domain. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/MSH6ID344ch2p16.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MSH6"; WEB RESOURCE: Name=Hereditary non-polyposis colorectal cancer db; URL="http://www.nfdht.nl/"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/msh6/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
SCOP Domains: 48334 - DNA repair protein MutS, domain III 63748 - Tudor/PWWP/MBT 52540 - P-loop containing nucleoside triphosphate hydrolases 53150 - DNA repair protein MutS, domain II 55271 - DNA repair protein MutS, domain I
ModBase Predicted Comparative 3D Structure on P52701
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000710 meiotic mismatch repair GO:0006281 DNA repair GO:0006298 mismatch repair GO:0006974 cellular response to DNA damage stimulus GO:0008340 determination of adult lifespan GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage GO:0009411 response to UV GO:0016032 viral process GO:0016446 somatic hypermutation of immunoglobulin genes GO:0016447 somatic recombination of immunoglobulin gene segments GO:0045190 isotype switching GO:0045830 positive regulation of isotype switching GO:0045910 negative regulation of DNA recombination GO:0051096 positive regulation of helicase activity GO:0097193 intrinsic apoptotic signaling pathway GO:0043570 maintenance of DNA repeat elements
BC071594 - Homo sapiens mutS homolog 6 (E. coli), mRNA (cDNA clone IMAGE:4374146). U28946 - Human G/T mismatch binding protein (GTBP) mRNA, complete cds. D89646 - Homo sapiens GTBP mRNA for GTBP-ALT, complete cds. BC104665 - Homo sapiens mutS homolog 6 (E. coli), mRNA (cDNA clone IMAGE:6498529), partial cds. U54777 - Homo sapiens hMSH6 protein (MSH6) mRNA, complete cds. BC004246 - Homo sapiens mutS homolog 6 (E. coli), mRNA (cDNA clone MGC:10498 IMAGE:3629489), complete cds. AK308392 - Homo sapiens cDNA, FLJ98340. AK293921 - Homo sapiens cDNA FLJ55677 complete cds, highly similar to DNA mismatch repair protein MSH6. JD437937 - Sequence 418961 from Patent EP1572962. AB590153 - Synthetic construct DNA, clone: pFN21AE1305, Homo sapiens MSH6 gene for mutS homolog 6, without stop codon, in Flexi system. DQ892898 - Synthetic construct clone IMAGE:100005528; FLH191875.01X; RZPDo839H1177D mutS homolog 6 (E. coli) (MSH6) gene, encodes complete protein. AK304735 - Homo sapiens cDNA FLJ53432 complete cds, highly similar to DNA mismatch repair protein MSH6. AK130683 - Homo sapiens cDNA FLJ27173 fis, clone SYN01861, highly similar to DNA mismatch repair protein MSH6. Y16676 - Homo sapiens mRNA for sperm surface protein. HW297782 - JP 2013523126-A/25: MATERIALS AND METHODS RELATED TO MODULATION OF MISMATCH REPAIR AND GENOMIC STABILITY BY MIR-155. JA894001 - Sequence 25 from Patent EP2552547. JD357596 - Sequence 338620 from Patent EP1572962. HW469366 - JP 2014500871-A/13: MATERIALS AND METHODS RELATED TO MICRORNA-21, MISMATCH REPAIR, AND COLORECTAL CANCER.
Biochemical and Signaling Pathways
Reactome (by CSHL, EBI, and GO)
Protein P52701 (Reactome details) participates in the following event(s):
R-HSA-5444516 Formation of MSH2:MSH6 Complex R-HSA-5358525 MSH2:MSH6 binds 1 base mismatch or 1-2 base insertion/deletion loop R-HSA-5358912 MSH2:MSH6 exchanges ADP for ATP R-HSA-5358518 MLH1:PMS2 makes single strand incision near 1-2 base mismatch R-HSA-5358510 MSH2:MSH6 recruits MLH1:PMS2 to mismatch and interacts with PCNA R-HSA-5358597 EXO1 interacts with MSH2:MSH6 (MutSalpha) and MLH1:PMS2 (MutLalpha) R-HSA-5358565 Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) R-HSA-5632928 Defective Mismatch Repair Associated With MSH2 R-HSA-5358508 Mismatch Repair R-HSA-5423599 Diseases of Mismatch Repair (MMR) R-HSA-73894 DNA Repair R-HSA-1643685 Disease
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
