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MSH6

Protein FULL name:

DNA mismatch repair protein Msh6 [Homo sapiens].


MSH6 (Homo sapiens) is product of expression of MSH6 gene.

Human diseases related to this protein:

MSH6 is involved in:

MMR in Homo sapiens

Keywords:



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: P49662:CASP4; NbExp=1; IntAct=EBI-395529, EBI-1057327; P43246:MSH2; NbExp=1; 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:600678]. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPphenotype (also called Lynch syndrome). Most families with clinically recognized HNPhave mutations in either MLH1 or MSH2 genes. HNPis 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. HNPis reported to be the most common form of inherited colorectal cancer in the Western world. Cancers in HNPoriginate within benign neoplastic polyps termed adenomas. Clinically, HNPis 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 HNPand 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 [MIM:608089].

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; [LINK]

WEB RESOURCE: Name=GeneReviews; [LINK]

WEB RESOURCE: Name=Hereditary non-polyposis colorectal cancer db; [LINK]

WEB RESOURCE: Name=NIEHS-SNPs; [LINK]


This protein can be a part of a given complexes:
NCBI GenPept GI number(s): 4504191
Species: Homo sapiens

Links to other databases:

Database ID Link
Uniprot P52701 P52701
PFAM: - P52701 (Link - using uniprot id)
InterPro: - P52701 (Link - using uniprot id)
CATH: None  
SCOP: None  
PDB: - -


Protein sequence:
MSRQSTLYSFFPKSPALSDANKASARASREGGRAAAAPGASPSPGGDAAW
SEAGPGPRPLARSASPPKAKNLNGGLRRSVAPAAPTSCDFSPGDLVWAKM
EGYPWWPCLVYNHPFDGTFIREKGKSVRVHVQFFDDSPTRGWVSKRLLKP
YTGSKSKEAQKGGHFYSAKPEILRAMQRADEALNKDKIKRLELAVCDEPS
EPEEEEEMEVGTTYVTDKSEEDNEIESEEEVQPKTQGSRRSSRQIKKRRV
ISDSESDIGGSDVEFKPDTKEEGSSDEISSGVGDSESEGLNSPVKVARKR
KRMVTGNGSLKRKSSRKETPSATKQATSISSETKNTLRAFSAPQNSESQA
HVSGGGDDSSRPTVWYHETLEWLKEEKRRDEHRRRPDHPDFDASTLYVPE
DFLNSCTPGMRKWWQIKSQNFDLVICYKVGKFYELYHMDALIGVSELGLV
FMKGNWAHSGFPEIAFGRYSDSLVQKGYKVARVEQTETPEMMEARCRKMA
HISKYDRVVRREICRIITKGTQTYSVLEGDPSENYSKYLLSLKEKEEDSS
GHTRAYGVCFVDTSLGKFFIGQFSDDRHCSRFRTLVAHYPPVQVLFEKGN
LSKETKTILKSSLSCSLQEGLIPGSQFWDASKTLRTLLEEEYFREKLSDG
IGVMLPQVLKGMTSESDSIGLTPGEKSELALSALGGCVFYLKKCLIDQEL
LSMANFEEYIPLDSDTVSTTRSGAIFTKAYQRMVLDAVTLNNLEIFLNGT
NGSTEGTLLERVDTCHTPFGKRLLKQWLCAPLCNHYAINDRLDAIEDLMV
VPDKISEVVELLKKLPDLERLLSKIHNVGSPLKSQNHPDSRAIMYEETTY
SKKKIIDFLSALEGFKVMCKIIGIMEEVADGFKSKILKQVISLQTKNPEG
RFPDLTVELNRWDTAFDHEKARKTGLITPKAGFDSDYDQALADIRENEQS
LLEYLEKQRNRIGCRTIVYWGIGRNRYQLEIPENFTTRNLPEEYELKSTK
KGCKRYWTKTIEKKLANLINAEERRDVSLKDCMRRLFYNFDKNYKDWQSA
VECIAVLDVLLCLANYSRGGDGPMCRPVILLPEDTPPFLELKGSRHPCIT
KTFFGDDFIPNDILIGCEEEEQENGKAYCVLVTGPNMGGKSTLMRQAGLL
AVMAQMGCYVPAEVCRLTPIDRVFTRLGASDRIMSGESTFFVELSETASI
LMHATAHSLVLVDELGRGTATFDGTAIANAVVKELAETIKCRTLFSTHYH
SLVEDYSQNVAVRLGHMACMVENECEDPSQETITFLYKFIKGACPKSYGF
NAARLANLPEEVIQKGHRKAREFEKMNQSLRLFREVCLASERSTVDAEAV
HKLLTLIKEL

MSH6 (Homo sapiens) is able to recognize following damages:
MSH6 (Homo sapiens) belongs to following protein families:
References:

Title Authors Journal
GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Palombo F, Gallinari P, Iaccarino I, Lettieri T, Hughes M, D'Arrigo A, Truong O, Hsuan JJ, Jiricny J Science June 1, 1995
Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells. Drummond JT, Li GM, Longley MJ, Modrich P Science June 1, 1995
Mutations of GTBP in genetically unstable cells. Papadopoulos N, Nicolaides NC, Liu B, Parsons R, Lengauer C, Palombo F, D'Arrigo A, Markowitz S, Willson JK, Kinzler KW, et al. Science June 1, 1995
Molecular cloning of the N-terminus of GTBP. Nicolaides NC, Palombo F, Kinzler KW, Vogelstein B, Jiricny J Genomics Jan. 1, 1996
hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Acharya S, Wilson T, Gradia S, Kane MF, Guerrette S, Marsischky GT, Kolodner R, Fishel R Proc Natl Acad Sci U S A Nov. 26, 1996
Alternative splicing of GTBP in normal human tissues. Shiwaku HO, Wakatsuki S, Mori Y, Fukushige S, Horii A DNA Res Oct. 31, 1997
Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M, Igari T, Koike M, Chiba M, Mori T Nat Genet Nov. 1, 1997
hMSH2 and hMSH6 play distinct roles in mismatch binding and contribute differently to the ATPase activity of hMutSalpha. Iaccarino I, Marra G, Palombo F, Jiricny J EMBO J May 1, 1998
Nucleotide-promoted release of hMutSalpha from heteroduplex DNA is consistent with an ATP-dependent translocation mechanism. Blackwell LJ, Martik D, Bjornson KP, Bjornson ES, Modrich P J Biol Chem Nov. 27, 1998
DNA-dependent activation of the hMutSalpha ATPase. Blackwell LJ, Bjornson KP, Modrich P J Biol Chem Nov. 27, 1998
Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer. Wang Q, Lasset C, Desseigne F, Saurin JC, Maugard C, Navarro C, Ruano E, Descos L, Trillet-Lenoir V, Bosset JF, Puisieux A Hum Genet Jan. 1, 1999
Functional analysis of human MutSalpha and MutSbeta complexes in yeast. Clark AB, Cook ME, Tran HT, Gordenin DA, Resnick MA, Kunkel TA Nucleic Acids Res Jan. 1, 1999
hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA. Gradia S, Subramanian D, Wilson T, Acharya S, Makhov A, Griffith J, Fishel R Mol Cell Jan. 1, 1999
Frequent microsatellite instability and mismatch repair gene mutations in young Chinese patients with colorectal cancer. Chan TL, Yuen ST, Chung LP, Ho JW, Kwan KY, Chan AS, Ho JC, Leung SY, Wyllie AH J Natl Cancer Inst July 21, 1999
Germ-line msh6 mutations in colorectal cancer families. Kolodner RD, Tytell JD, Schmeits JL, Kane MF, Gupta RD, Weger J, Wahlberg S, Fox EA, Peel D, Ziogas A, Garber JE, Syngal S, Anton-Culver H, Li FP Cancer Res Oct. 15, 1999
Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Wu Y, Berends MJ, Mensink RG, Kempinga C, Sijmons RH, van Der Zee AG, Hollema H, Kleibeuker JH, Buys CH, Hofstra RM Am J Hum Genet Nov. 1, 1999
The role of mismatched nucleotides in activating the hMSH2-hMSH6 molecular switch. Gradia S, Acharya S, Fishel R J Biol Chem Jan. 11, 2000
Sequence analysis of the mismatch repair gene hMSH6 in the germline of patients with familial and sporadic colorectal cancer. Plaschke J, Kruppa C, Tischler R, Bocker T, Pistorius S, Dralle H, Ruschoff J, Saeger HD, Fishel R, Schackert HK Int J Cancer March 1, 2000
BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J Genes Dev April 15, 2000
Do MSH6 mutations contribute to double primary cancers of the colorectum and endometrium? Charames GS, Millar AL, Pal T, Narod S, Bapat B Hum Genet Dec. 1, 2000
Germline and somatic mutations in hMSH6 and hMSH3 in gastrointestinal cancers of the microsatellite mutator phenotype. Ohmiya N, Matsumoto S, Yamamoto H, Baranovskaya S, Malkhosyan SR, Perucho M Gene July 11, 2001
A role for MLH3 in hereditary nonpolyposis colorectal cancer. Wu Y, Berends MJ, Sijmons RH, Mensink RG, Verlind E, Kooi KA, van der Sluis T, Kempinga C, van dDer Zee AG, Hollema H, Buys CH, Kleibeuker JH, Hofstra RM Nat Genet Oct. 1, 2001
Involvement of hMSH6 in the development of hereditary and sporadic colorectal cancer revealed by immunostaining is based on germline mutations, but rarely on somatic inactivation. Plaschke J, Kruger S, Pistorius S, Theissig F, Saeger HD, Schackert HK Int J Cancer Jan. 10, 2002
Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. Berends MJ, Wu Y, Sijmons RH, Mensink RG, van der Sluis T, Hordijk-Hos JM, de Vries EG, Hollema H, Karrenbeld A, Buys CH, van der Zee AG, Hofstra RM, Kleibeuker JH Am J Hum Genet Feb. 1, 2002
Two mismatch repair gene mutations found in a colon cancer patient--which one is pathogenic? Kariola R, Otway R, Lonnqvist KE, Raevaara TE, Macrae F, Vos YJ, Kohonen-Corish M, Hofstra RM, Nystrom-Lahti M Hum Genet Jan. 1, 2003
Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. Wagner A, Barrows A, Wijnen JT, van der Klift H, Franken PF, Verkuijlen P, Nakagawa H, Geugien M, Jaghmohan-Changur S, Breukel C, Meijers-Heijboer H, Morreau H, van Puijenbroek M, Burn J, Coronel S, Kinarski Y, Okimoto R, Watson P, Lynch JF, de la Chapelle A, Lynch HT, Fodde R Am J Hum Genet May 1, 2003
MSH6 germline mutations are rare in colorectal cancer families. Peterlongo P, Nafa K, Lerman GS, Glogowski E, Shia J, Ye TZ, Markowitz AJ, Guillem JG, Kolachana P, Boyd JA, Offit K, Ellis NA Int J Cancer Nov. 20, 2003
Eight novel MSH6 germline mutations in patients with familial and nonfamilial colorectal cancer selected by loss of protein expression in tumor tissue. Plaschke J, Kruger S, Dietmaier W, Gebert J, Sutter C, Mangold E, Pagenstecher C, Holinski-Feder E, Schulmann K, Moslein G, Ruschoff J, Engel C, Evans G, Schackert HK Hum Mutat March 1, 2004
Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in northern Sweden. Cederquist K, Emanuelsson M, Goransson I, Holinski-Feder E, Muller-Koch Y, Golovleva I, Gronberg H Int J Cancer April 10, 2004
The mismatch DNA repair heterodimer, hMSH2/6, regulates BLM helicase. Yang Q, Zhang R, Wang XW, Linke SP, Sengupta S, Hickson ID, Pedrazzi G, Perrera C, Stagljar I, Littman SJ, Modrich P, Harris CC Oncogene May 6, 2004
Large-scale characterization of HeLa cell nuclear phosphoproteins. Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villen J, Li J, Cohn MA, Cantley LC, Gygi SP Proc Natl Acad Sci U S A Aug. 17, 2004
The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J Genome Res Oct. 1, 2004
Germline mutations in MLH1, MSH2 and MSH6 in Korean hereditary non-polyposis colorectal cancer families. Shin YK, Heo SC, Shin JH, Hong SH, Ku JL, Yoo BC, Kim IJ, Park JG Hum Mutat Oct. 1, 2004
MSH6 missense mutations are often associated with no or low cancer susceptibility. Kariola R, Hampel H, Frankel WL, Raevaara TE, de la Chapelle A, Nystrom-Lahti M Br J Cancer Oct. 4, 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. Plaschke J, Engel C, Kruger S, Holinski-Feder E, Pagenstecher C, Mangold E, Moeslein G, Schulmann K, Gebert J, von Knebel Doeberitz M, Ruschoff J, Loeffler M, Schackert HK J Clin Oncol Nov. 15, 2004
hMutS alpha is protected from ubiquitin-proteasome-dependent degradation by atypical protein kinase C zeta phosphorylation. Hernandez-Pigeon H, Quillet-Mary A, Louat T, Schambourg A, Humbert O, Selves J, Salles B, Laurent G, Lautier D J Mol Biol April 22, 2005
Phosphoproteome analysis of the human mitotic spindle. Nousiainen M, Sillje HH, Sauer G, Nigg EA, Korner R Proc Natl Acad Sci U S A April 4, 2006
A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Beausoleil SA, Villen J, Gerber SA, Rush J, Gygi SP Nat Biotechnol Oct. 1, 2006
Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M Cell Nov. 3, 2006
Patterns of somatic mutation in human cancer genomes. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR Nature March 8, 2007
ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ Science May 25, 2007
Structure of the human MutSalpha DNA lesion recognition complex. Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS Mol Cell May 25, 2007
Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra. Yu LR, Zhu Z, Chan KC, Issaq HJ, Dimitrov DS, Veenstra TD J Proteome Res Nov. 1, 2007
Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis. Cantin GT, Yi W, Lu B, Park SK, Xu T, Lee JD, Yates JR 3rd J Proteome Res March 1, 2008
Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer. Barnetson RA, Cartwright N, van Vliet A, Haq N, Drew K, Farrington S, Williams N, Warner J, Campbell H, Porteous ME, Dunlop MG Hum Mutat March 1, 2008
A quantitative atlas of mitotic phosphorylation. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP Proc Natl Acad Sci U S A Aug. 5, 2008
Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Daub H, Olsen JV, Bairlein M, Gnad F, Oppermann FS, Korner R, Greff Z, Keri G, Stemmann O, Mann M Mol Cell Aug. 8, 2008
Lysine acetylation targets protein complexes and co-regulates major cellular functions. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M Science Aug. 14, 2009


Last modification of this entry: Nov. 11, 2010.

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