MSH6 (mutS homolog 6 (E. Coli))

2006-11-01   Sreeparna Banerjee 

Department of Biology, Office: Z-16\\\/Lab: B-59, Middle East Technical University, 06531 Ankara, Turkey

Identity

HGNC
LOCATION
2p16.3
LOCUSID
ALIAS
GTBP,GTMBP,HNPCC5,HSAP,MMRCS3,p160
FUSION GENES

DNA/RNA

Note

The genes for MSH2 and MSH6 which form the major mismatch recognition MutSalpha complex functional in the mismatch repair (MMR) pathway are located within 1 Mb of each other. MSH2 and MSH6 may have been produced by duplication of a primordial mutS repair gene.
Atlas Image
Exons are represented by gray boxes (in scale) with exon numbers on the bottom. The arrows show the ATG and the stop codons respectively.

Description

MSH6 gene maps to NC_000002.10 and spans a region of 23.8 kilo bases.
MSH6 has 10 exons, the sizes being 347, 197, 170, 2545, 266, 119, 89, 155, 200 and 176 bps.

Transcription

Human MSH6 gene is transcriptionally upregulated 2.5 fold at late G1/early S phase while the amount of protein remains unchanged during the whole cell cycle.
The promoter region has a high GC content, as well as multiple start sites. Sequence analysis of 3.9 kb of the 5-upstream region of the MSH6 gene revealed the absence of TATAA- or CAAT-boxes. Seven consensus binding sequences for the ubiquitous transcription factor Sp1 were found in the promoter region. This factor is implicated in positioning the RNA polymerase II complex at the transcriptional start sites of promoters lacking TATA- and CAAT-boxes. The proximal promoter region of MSH6 gene also contains several consensus binding sites of the embryonic TEA domain-containing factor ETF. This transcription factor has also been reported to stimulate transcription from promoters lacking the TATA box. In addition, the trancription of MSH6 gene is downregulated by CpG methylation of the promoter region.
Three common polymorphic variants (-557 T G, -448 G A, and -159 C T) of the MSH6 promoter have been identified in which different Sp1 sites were inactivated by single-nucleotide polymorphisms (SNPs) resulting in altered promoter activity.

Pseudogene

No pseudogene has been reported for the MSH6 gene.

Proteins

Note

Eukaryotic MutSalpha is a heterodimer of the 100-kDa MSH2 and the 160-kDa MSH6 that participates in the mismatch repair pathway. The proteins are required for single base and frameshift mispair specific binding, a result consistent with the finding that tumour-derived cell lines devoid of either protein have a mutator phenotype.

Description

The MSH6 protein maps to NP_000170 and has 1360 amino acids. The molecular weight is 152786 Da. The protein contains a highly conserved helix-turn-helix domain associated with a Walker-A motif (an adenine nucleotide and magnesium binding motif) with ATPase activity.
The breast cancer 1 gene (BRCA1) product is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. This complex is called BASC, for BRCA1-associated genome surveillance complex and the mismatch repair protein MSH6 was found to be a part of this complex.

Localisation

The subcellular localisation of MSH6 is the nucleus.

Function

hMSH6 gene product with hMSH2, hMSH3 gene products play role in strand specific repair of DNA replication errors. Studies show that hMSH2-hMSH6 complex functions in the recognition step of the repair of base-base mismatches or single frameshifts. The ADP/ATP binding domain of the heterodimer and the associated ATPase activity function to regulate mismatch binding as a molecular switch. Both MSH2 and MSH6 can simultaneously bind ATP. The MSH6 subunit contains the high-affinity ATP binding site and MSH2 contains a high-affinity ADP binding site. Stable binding of ATP to MSH6 results in a decreased affinity of MSH2 for ADP, and binding to mispaired DNA stabilizes the binding of ATP to MSH6. Mispair binding encourages a dual-occupancy state with ATP bound to Msh6 and Msh2; following which there is a hydrolysis-independent sliding along DNA. Subsequent steps result in the excision of the mispaired region followed by DNA synthesis and ligation.

Homology

H.sapiens: MSH6 (mutS homolog 6 (E. coli)).
C.familiaris: LOC474585 (similar to mutS homolog 6).
M.musculus: Msh6 (mutS homolog 6 (E. coli)).
C.elegans: msh-6 (MSH (MutS Homolog) family).
S.pombe: SPCC285.16c (hypothetical protein).
S.cerevisiae: MSH6 (Mismatch repair protein).
A.thaliana: MSH6 (MSH6).

Mutations

Note

The MSH6 gene plays a role in the development of inherited cancers, especially the colorectum and endometrial cancers.

Germinal

MSH6 germline mutations have variable penetration. Atypical hereditary non polyposis colorectal cancer (HNPCC) can result from germline mutations in MSH6; however, disease-causing germline mutations of MSH6 are rare in HNPCC and HNPCC-like families. Other studies have indicated that germline MSH6 mutations may contribute to a subset of early-onset colorectal cancer.

Somatic

The involvement of somatic or epigenetic inactivation of hMSH6 is rare in colorectal cancer and missense mutations in MSH6 are often clinically innocuous or have a low penetrance. However, somatic mutations of MSH6 have been shown to confer resistance to alkylating agents such as temozolomide in malignant gliomas in vivo. This concurrently results in accelerated mutagenesis in resistant clones as a consequence of continued exposure to alkylating agents in the presence of defective mismatch repair. Therefore, when MSH6 is inactivated in gliomas, there is a change in status of the alkylating agents from induction of tumour cell death to promotion of neoplastic progression.

Implicated in

Entity name
hereditary non polyposis colorectal cancer
Disease
Mutations in the mismatch repair genes MSH2, MSH6, < CC: TXT: MLH1 ID: 149> and PMS2 results in hereditary non polyposis colorectal cancer (HNPCC, Lynch syndrome). Individuals predisposed to this syndrome have increased lifetime risk of developing colorectal, endometrial and other cancers. The resulting mismatch repair deficiency leads to microsatellite instability which is the hallmark of tumors arising within this syndrome, as well as a variable proportion of sporadic tumors.
Clinically, HNPCC can be divided into two subgroups:
Type I: a young onset age for hereditary colorectal cancer, and carcinoma of the proximal colon.
Type II: patients are susceptible to cancers in tissues such as the colon, uterus, ovary, breast, stomach, small intestine and skin.
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.
Entity name
Turcot Syndrome
Disease
Turcot syndrome is a condition whereby central nervous system malignant tumours are associated with familial colorectal cancer. A homozygous mutation in MSH6 has been reported in a family with childhood-onset brain tumour, lymphoma, colorectal cancer, and neurofibromatosis type 1 phenotype.
Entity name
Colorectal cancer.
Disease
Mutations in four mismatch repair genes MSH2, MLH1, MSH6, and PMS2, have been convincingly linked to susceptibility of hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome. Of the 500 different HNPCC-associated MMR gene mutations known, approximately 10% are associated with mutations in the MSH6 gene.
Entity name
Endometrial cancer
Disease
Germline mutations in the MSH6 gene are often observed in HNPCC-like families with an increased frequency of endometrial cancer. Sequence analysis of the MSH6 coding region revealed the presence of three putative missense mutations in patients with atypical family histories that do not meet HNPCC criteria. MSH6 mutations may contribute to the etiology of double primary carcinomas of the colorectum and endometrium.
Entity name
Ovarian cancer
Disease
Late-onset endometrioid type of ovarian cancer can be linked to MSH6 germline mutations.
Entity name
Lung cancer
Disease
Early onset lung cancer (before age 50) has been associated with polymorphisms in the MSH6 gene. Cadmium, an environmental and occupational carcinogen associated with lung cancer development was shown to inhibit the ATPase activity of MSH2-MSH6 heterodimer.
Entity name
Breast cancer
Disease
Mutations in the MSH6 gene are not usually connected with breast cancer, even when associated with endometrial or colorectal cancer.

Bibliography

Pubmed IDLast YearTitleAuthors
164342082006The genetics of HNPCC: application to diagnosis and screening.Abdel-Rahman WM et al
89429851996hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6.Acharya S et al
157460002005Cadmium inhibits mismatch repair by blocking the ATPase activity of the MSH2-MSH6 complex.Banerjee S et al
168074122006Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.Barnetson RA et al
111539172000Do MSH6 mutations contribute to double primary cancers of the colorectum and endometrium?Charames GS et al
145859612003Regulation of the human MSH6 gene by the Sp1 transcription factor and alteration of promoter activity and expression by polymorphisms.Gazzoli I et al
94285221997The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch.Gradia S et al
100782081999hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA.Gradia S et al
160005622005A homozygous mutation in MSH6 causes Turcot syndrome.Hegde MR et al
166187162006A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy.Hunter C et al
166123262006The multifaceted mismatch-repair system.Jiricny J et al
153542102004MSH6 missense mutations are often associated with no or low cancer susceptibility.Kariola R et al
171081462006DNA repair and cell cycle control genes and the risk of young-onset lung cancer.Landi S et al
166008682006Inhibition of Msh6 ATPase activity by mispaired DNA induces a Msh2(ATP)-Msh6(ATP) state capable of hydrolysis-independent movement along DNA.Mazur DJ et al
76042651995GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells.Palombo F et al
76042661995Mutations of GTBP in genetically unstable cells.Papadopoulos N et al
161363822005Lynch syndrome genes.Peltomäki P et al
145206942003MSH6 germline mutations are rare in colorectal cancer families.Peterlongo P et al
169409832006MSH6 germline mutations in early-onset colorectal cancer patients without family history of the disease.Pinto C et al
118077912002Involvement 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 et al
156605262005Inherited susceptibility to colorectal cancer.Rowley PT et al
162703832005Low prevalence of germline hMSH6 mutations in colorectal cancer families from Spain.Sánchez de Abajo A et al
123767422002Ovarian cancer of endometrioid type as part of the MSH6gene mutation phenotype.Suchy J et al
117469862002Identification and functional characterization of the promoter region of the human MSH6 gene.Szadkowski M et al
158051512005No MSH6 germline mutations in breast cancer families with colorectal and/or endometrial cancer.Vahteristo P et al
107831652000BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.Wang Y et al

Other Information

Locus ID:

NCBI: 2956
MIM: 600678
HGNC: 7329
Ensembl: ENSG00000116062

Variants:

dbSNP: 2956
ClinVar: 2956
TCGA: ENSG00000116062
COSMIC: MSH6

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000116062ENST00000234420P52701
ENSG00000116062ENST00000411819C9J7Y7
ENSG00000116062ENST00000420813C9JH55
ENSG00000116062ENST00000445503F8WAX8
ENSG00000116062ENST00000455383C9J8Y8
ENSG00000116062ENST00000456246F8W7G9
ENSG00000116062ENST00000538136P52701
ENSG00000116062ENST00000540021P52701
ENSG00000116062ENST00000614496P52701
ENSG00000116062ENST00000616033A0A087WWJ1
ENSG00000116062ENST00000622629A0A087WYT6
ENSG00000116062ENST00000652107A0A494C0M1

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45

Pathways

PathwaySourceExternal ID
Mismatch repairKEGGko03430
Colorectal cancerKEGGko05210
Mismatch repairKEGGhsa03430
Pathways in cancerKEGGhsa05200
Colorectal cancerKEGGhsa05210
BRCA1-associated genome surveillance complex (BASC)KEGGhsa_M00295
BRCA1-associated genome surveillance complex (BASC)KEGGM00295
DNA RepairREACTOMER-HSA-73894
Mismatch RepairREACTOMER-HSA-5358508
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)REACTOMER-HSA-5358565
Platinum drug resistanceKEGGko01524
Platinum drug resistanceKEGGhsa01524

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA443761Colorectal Neoplasms, Hereditary NonpolyposisDiseaseLiterature, MultilinkAnnotationassociated23788249

References

Pubmed IDYearTitleCitations
216426822011Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.198
236222432013The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα.194
168853852006Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients.149
198616712009Risk of pancreatic cancer in families with Lynch syndrome.141
198616712009Risk of pancreatic cancer in families with Lynch syndrome.141
195841612009MSH6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance.117
168074122006Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.108
200289932010Risks of Lynch syndrome cancers for MSH6 mutation carriers.106
196223572009Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome.101
223319442012Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study.95

Citation

Sreeparna Banerjee

MSH6 (mutS homolog 6 (E. Coli))

Atlas Genet Cytogenet Oncol Haematol. 2006-11-01

Online version: http://atlasgeneticsoncology.org/gene/344/msh6