MSH6

Last updated

MSH6
Protein MSH6 PDB 2gfu.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases MSH6 , mutS homolog 6, GTBP, GTMBP, HNPCC5, HSAP, p160, MMRCS3, MSH-6
External IDs OMIM: 600678; MGI: 1343961; HomoloGene: 149; GeneCards: MSH6; OMA:MSH6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2956

17688

Ensembl

ENSG00000116062

ENSMUSG00000005370

UniProt

P52701

P54276

RefSeq (mRNA)

NM_000179
NM_001281492
NM_001281493
NM_001281494

NM_010830

RefSeq (protein)

NP_000170
NP_001268421
NP_001268422
NP_001268423

NP_034960

Location (UCSC) Chr 2: 47.7 – 47.81 Mb Chr 17: 88.28 – 88.3 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.

Contents

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

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. [5] Thus, GTBP took on the name human MSH6, or hMSH6.

Structure

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. [6] 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. [7]

Function

Importance of mismatch repair

Mismatches commonly occur as a result of DNA replication errors, genetic recombination, or other chemical and physical factors. [8] 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. [6] [9] hMSH6 combines with hMSH2 to form the active protein complex, hMutS alpha, also called hMSH2-hMSH6.

Mismatch recognition

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. [10] 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. [9] The ADP-->ATP exchange causes a conformational change to convert hMutS alpha into a sliding clamp that can diffuse along the DNA backbone. [9] 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. [9]

Cancer

Although mutations in hMSH2 cause a strong general mutator phenotype, mutations in hMSH6 cause only a modest mutator phenotype. [5] 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. [5]

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. [5] HNPCC is most commonly caused by mutations in hMSH2 and hMLH1, but mutations in hMSH6 are linked to an atypical form of HNPCC. [11] 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. [11]

Epigenetic control of MSH6 in cancer

Two microRNAs, miR21 and miR-155, target the DNA mismatch repair (MMR) genes hMSH6 and hMSH2 , to cause reduced expression of their proteins. [12] [13] If one or the other of these two microRNAs is over-expressed, hMSH2 and hMSH6 proteins are under-expressed, resulting in reduced DNA mismatch repair and increased microsatellite instability.

One of these microRNAs, miR21, is regulated by the epigenetic methylation state of the CpG islands in one or the other of its two promoter regions. [14] Hypomethylation of its promoter region is associated with increased expression of an miRNA. [15] High expression of a microRNA causes repression of its target genes (see microRNA silencing of genes). In 66% to 90% of colon cancers, miR-21 was over-expressed, [12] and generally the measured level of hMSH2 was decreased (and hMSH6 is unstable without hMSH2 [13] ).

The other microRNA, miR-155, is regulated both by epigenetic methylation of the CpG islands in its promoter region [16] and by epigenetic acetylation of histones H2A and H3 at the miR-155 promoter (where acetylation increases transcription). [17] Measured by two different methods, miR-155 was over-expressed in sporadic colorectal cancers by either 22% or 50%. [13] When miR-155 was elevated, hMSH2 was under-expressed in 44% to 67% of the same tissues (and hMSH6 is likely under-expressed as well, and also unstable in the absence of hMSH2). [13]

Interactions

MSH6 has been shown to interact with MSH2, [18] [19] [20] [21] [22] PCNA [23] [24] [25] and BRCA1. [18] [26]

See also

Related Research Articles

<span class="mw-page-title-main">Hereditary nonpolyposis colorectal cancer</span> Autosomal dominant genetic condition associated with a high risk of cancer in the colon

Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer.

<span class="mw-page-title-main">Neoplasm</span> Tumor or other abnormal growth of tissue

A neoplasm is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists in growing abnormally, even if the original trigger is removed. This abnormal growth usually forms a mass, which may be called a tumour or tumor.

<span class="mw-page-title-main">Mismatch repair cancer syndrome</span> Medical condition

Mismatch repair cancer syndrome (MMRCS) is a cancer syndrome associated with biallelic DNA mismatch repair mutations. It is also known as Turcot syndrome and by several other names.

<span class="mw-page-title-main">DNA mismatch repair</span> System for fixing base errors of DNA replication

DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.

<span class="mw-page-title-main">MUTYH</span> Protein-coding gene in the species Homo sapiens

MUTYH is a human gene that encodes a DNA glycosylase, MUTYH glycosylase. It is involved in oxidative DNA damage repair and is part of the base excision repair pathway. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a common form of oxidative DNA damage.

In molecular biology, an exonic splicing enhancer (ESE) is a DNA sequence motif consisting of 6 bases within an exon that directs, or enhances, accurate splicing of heterogeneous nuclear RNA (hnRNA) or pre-mRNA into messenger RNA (mRNA).

<span class="mw-page-title-main">Muir–Torre syndrome</span> Medical condition

Muir–Torre syndrome is a rare hereditary, autosomal dominant cancer syndrome that is thought to be a subtype of HNPCC. Individuals are prone to develop cancers of the colon, genitourinary tract, and skin lesions, such as keratoacanthomas and sebaceous tumors. The genes affected are MLH1, MSH2, and more recently, MSH6, and are involved in DNA mismatch repair.

<span class="mw-page-title-main">MSH2</span> Protein-coding gene in the species Homo sapiens

DNA mismatch repair protein Msh2 also known as MutS homolog 2 or MSH2 is a protein that in humans is encoded by the MSH2 gene, which is located on chromosome 2. MSH2 is a tumor suppressor gene and more specifically a caretaker gene that codes for a DNA mismatch repair (MMR) protein, MSH2, which forms a heterodimer with MSH6 to make the human MutSα mismatch repair complex. It also dimerizes with MSH3 to form the MutSβ DNA repair complex. MSH2 is involved in many different forms of DNA repair, including transcription-coupled repair, homologous recombination, and base excision repair.

<span class="mw-page-title-main">MLH1</span> Protein-coding gene in humans

DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. The gene is commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae.

<span class="mw-page-title-main">Mismatch repair endonuclease PMS2</span> Protein-coding gene in the species Homo sapiens

Mismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the PMS2 gene.

<span class="mw-page-title-main">Methylated-DNA-protein-cysteine methyltransferase</span> Mammalian protein found in Homo sapiens

Methylated-DNA--protein-cysteine methyltransferase(MGMT), also known as O6-alkylguanine DNA alkyltransferaseAGT, is a protein that in humans is encoded by the MGMT gene. MGMT is crucial for genome stability. It repairs the naturally occurring mutagenic DNA lesion O6-methylguanine back to guanine and prevents mismatch and errors during DNA replication and transcription. Accordingly, loss of MGMT increases the carcinogenic risk in mice after exposure to alkylating agents. The two bacterial isozymes are Ada and Ogt.

<span class="mw-page-title-main">Exonuclease 1</span> Protein-coding gene in the species Homo sapiens

Exonuclease 1 is an enzyme that in humans is encoded by the EXO1 gene.

<span class="mw-page-title-main">MSH3</span> Protein-coding gene in the species Homo sapiens

DNA mismatch repair protein, MutS Homolog 3 (MSH3) is a human homologue of the bacterial mismatch repair protein MutS that participates in the mismatch repair (MMR) system. MSH3 typically forms the heterodimer MutSβ with MSH2 in order to correct long insertion/deletion loops and base-base mispairs in microsatellites during DNA synthesis. Deficient capacity for MMR is found in approximately 15% of colorectal cancers, and somatic mutations in the MSH3 gene can be found in nearly 50% of MMR-deficient colorectal cancers.

<span class="mw-page-title-main">MBD4</span> Protein-coding gene in the species Homo sapiens

Methyl-CpG-binding domain protein 4 is a protein that in humans is encoded by the MBD4 gene.

<span class="mw-page-title-main">PMS1</span> Protein-coding gene in humans

PMS1 protein homolog 1 is a protein that in humans is encoded by the PMS1 gene.

<span class="mw-page-title-main">MSH5</span> Protein-coding gene in the species Homo sapiens

MutS protein homolog 5 is a protein that in humans is encoded by the MSH5 gene.

<span class="mw-page-title-main">MLH3</span> Protein-coding gene in humans

DNA mismatch repair protein Mlh3 is a protein that in humans is encoded by the MLH3 gene.

Mouse models of colorectal cancer and intestinal cancer are experimental systems in which mice are genetically manipulated, fed a modified diet, or challenged with chemicals to develop malignancies in the gastrointestinal tract. These models enable researchers to study the onset, progression of the disease, and understand in depth the molecular events that contribute to the development and spread of colorectal cancer. They also provide a valuable biological system, to simulate human physiological conditions, suitable for testing therapeutics.

<span class="mw-page-title-main">MutS-1</span>

MutS is a mismatch DNA repair protein, originally described in Escherichia coli.

Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000116062 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000005370 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 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.
  6. 1 2 Fishel R, Kolodner RD (1995). "Identification of mismatch repair genes and their role in the development of cancer". Current Opinion in Genetics & Development. 5 (3): 382–95. doi:10.1016/0959-437X(95)80055-7. PMID   7549435.
  7. ↑ Acharya S, et al. (1996). "hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6". PNAS. 93 (24): 13629–34. Bibcode:1996PNAS...9313629A. doi: 10.1073/pnas.93.24.13629 . PMC   19374 . PMID   8942985.
  8. ↑ Friedberg EC, Walker GC, Siede W. (1995). DNA repair and mutagenesis. American Society for Microbiology, Washington DC.
  9. 1 2 3 4 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.
  10. ↑ Gradia S, Acharya S, Fishel R (1997). "The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch". Cell. 91 (7): 995–1005. doi: 10.1016/S0092-8674(00)80490-0 . PMID   9428522. S2CID   3551402.
  11. 1 2 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. PMC   1734864 . PMID   11333868.
  12. 1 2 Valeri N, Gasparini P, Braconi C, Paone A, Lovat F, Fabbri M, Sumani KM, Alder H, Amadori D, Patel T, Nuovo GJ, Fishel R, Croce CM (2010). "MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2)". Proc. Natl. Acad. Sci. U.S.A. 107 (49): 21098–103. Bibcode:2010PNAS..10721098V. doi: 10.1073/pnas.1015541107 . PMC   3000294 . PMID   21078976.
  13. 1 2 3 4 Valeri N, Gasparini P, Fabbri M, Braconi C, Veronese A, Lovat F, Adair B, Vannini I, Fanini F, Bottoni A, Costinean S, Sandhu SK, Nuovo GJ, Alder H, Gafa R, Calore F, Ferracin M, Lanza G, Volinia S, Negrini M, McIlhatton MA, Amadori D, Fishel R, Croce CM (2010). "Modulation of mismatch repair and genomic stability by miR-155". Proc. Natl. Acad. Sci. U.S.A. 107 (15): 6982–7. Bibcode:2010PNAS..107.6982V. doi: 10.1073/pnas.1002472107 . PMC   2872463 . PMID   20351277.
  14. ↑ Baer C, Claus R, Plass C (2013). "Genome-wide epigenetic regulation of miRNAs in cancer". Cancer Res. 73 (2): 473–7. doi: 10.1158/0008-5472.CAN-12-3731 . PMID   23316035.
  15. ↑ Aure MR, Leivonen SK, Fleischer T, Zhu Q, Overgaard J, Alsner J, Tramm T, Louhimo R, Alnæs GI, Perälä M, Busato F, Touleimat N, Tost J, Børresen-Dale AL, Hautaniemi S, Troyanskaya OG, Lingjærde OC, Sahlberg KK, Kristensen VN (2013). "Individual and combined effects of DNA methylation and copy number alterations on miRNA expression in breast tumors". Genome Biol. 14 (11): R126. doi: 10.1186/gb-2013-14-11-r126 . PMC   4053776 . PMID   24257477.
  16. ↑ Krzeminski P, Sarasquete ME, Misiewicz-Krzeminska I, Corral R, Corchete LA, Martín AA, García-Sanz R, San Miguel JF, Gutiérrez NC (2015). "Insights into epigenetic regulation of microRNA-155 expression in multiple myeloma". Biochim. Biophys. Acta. 1849 (3): 353–66. doi:10.1016/j.bbagrm.2014.12.002. PMID   25497370.
  17. ↑ Chang S, Wang RH, Akagi K, Kim KA, Martin BK, Cavallone L, Haines DC, Basik M, Mai P, Poggi E, Isaacs C, Looi LM, Mun KS, Greene MH, Byers SW, Teo SH, Deng CX, Sharan SK (2011). "Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155". Nat. Med. 17 (10): 1275–82. doi:10.1038/nm.2459. PMC   3501198 . PMID   21946536.
  18. 1 2 Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (Apr 2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes & Development. 14 (8): 927–39. doi:10.1101/gad.14.8.927. PMC   316544 . PMID   10783165.
  19. ↑ Wang Y, Qin J (Dec 2003). "MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation". Proceedings of the National Academy of Sciences of the United States of America. 100 (26): 15387–92. Bibcode:2003PNAS..10015387W. doi: 10.1073/pnas.2536810100 . PMC   307577 . PMID   14657349.
  20. ↑ Guerrette S, Wilson T, Gradia S, Fishel R (Nov 1998). "Interactions of human hMSH2 with hMSH3 and hMSH2 with hMSH6: examination of mutations found in hereditary nonpolyposis colorectal cancer". Molecular and Cellular Biology. 18 (11): 6616–23. doi:10.1128/mcb.18.11.6616. PMC   109246 . PMID   9774676.
  21. ↑ Bocker T, Barusevicius A, Snowden T, Rasio D, Guerrette S, Robbins D, Schmidt C, Burczak J, Croce CM, Copeland T, Kovatich AJ, Fishel R (Feb 1999). "hMSH5: a human MutS homologue that forms a novel heterodimer with hMSH4 and is expressed during spermatogenesis". Cancer Research. 59 (4): 816–22. PMID   10029069.
  22. ↑ Acharya S, Wilson T, Gradia S, Kane MF, Guerrette S, Marsischky GT, Kolodner R, Fishel R (Nov 1996). "hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6". Proceedings of the National Academy of Sciences of the United States of America. 93 (24): 13629–34. Bibcode:1996PNAS...9313629A. doi: 10.1073/pnas.93.24.13629 . PMC   19374 . PMID   8942985.
  23. ↑ Kleczkowska HE, Marra G, Lettieri T, Jiricny J (Mar 2001). "hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci". Genes & Development. 15 (6): 724–36. doi:10.1101/gad.191201. PMC   312660 . PMID   11274057.
  24. ↑ Clark AB, Valle F, Drotschmann K, Gary RK, Kunkel TA (Nov 2000). "Functional interaction of proliferating cell nuclear antigen with MSH2-MSH6 and MSH2-MSH3 complexes". The Journal of Biological Chemistry. 275 (47): 36498–501. doi: 10.1074/jbc.C000513200 . PMID   11005803.
  25. ↑ Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T (Oct 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". The Journal of Biological Chemistry. 277 (43): 40362–7. doi: 10.1074/jbc.M206194200 . PMID   12171929.
  26. ↑ Wang Q, Zhang H, Guerrette S, Chen J, Mazurek A, Wilson T, Slupianek A, Skorski T, Fishel R, Greene MI (Aug 2001). "Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1". Oncogene. 20 (34): 4640–9. doi: 10.1038/sj.onc.1204625 . PMID   11498787.

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