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MSH2 is a mismatch repair (MMR) gene that forms a heterodimer with MSH6 to make the human MutSα mismatch repair complex. It also dimerizes with MSH3 to for the MutSβ DNA repair complex. Mutations in MSH2 are associated with Microsatellite instability and some cancers, especially with Hereditary nonpolyposis colorectal cancer (HNPCC). MSH2 has been implicated in many different forms of DNA repair, including Transcription-Coupled Repair,[1] homologous recombination,[2] and base excision repair.[3]
Biochemistry
[edit]Cancer Implications
[edit]Hereditary nonpolyposis colorectal cancer, sometimes referred to as Lynch syndrome, is inherited in an Autosomal dominant fashion, where inheritance of only one copy of a mutated mismatch repair gene is enough to cause disease phenotype. Mutations in the MSH2 gene account for ~40% of genetic alterations associated with this disease and is the leading cause, together with MSH1 mutations.[4] Mutations associated with HNPCC are broadly distributed in all domains of MSH2, and hypothetical functions of these mutations based on the crystal structure of the MutSα include protein-protein interactions, stability, allostery, MSH2-MSH6 interface, and DNA binding.[5]
The viability of MMR genes including MSH2 can be tracked via microsatellite instability, a biomarker test that analyzes short sequence repeats which are very difficult for cells to replicate without a functioning mismatch repair system. Because these sequences vary in the population, the actual number of copies of short sequence repeats does not matter, just that the number the patient does have is consistent from tissue to tissue and over time. This phenomena occurs because these sequences are prone to mistakes by the DNA replication complex, which then need to be fixed by the mismatch repair genes. If these are not working, over time either duplications or deletions of these sequences will occur, leading to different numbers of repeats in the same patient. 71% of HNPCC patients show microsatellite instability.[6] Detection methods for microsatellite instability include polymerase chain reaction (PCR) and immunohistochemical (IHC) methods, polymerase chain checking the DNA and immunohistochemical surveying mismatch repair protein levels. "Currently, there are evidences that universal testing fro MSI starting with either IHC or PCR-based MSI testing is cost effective, sensitive, specific and is generally widely accepted."[7]
Role in Mismatch Repair
[edit]p53, the tumor suppressor protein, has binding sites in the promoter region and first intron of MSH2.[8]
In eukaryotes from yeast to humans, MSH2 dimerizes with MSH6 to form the MutSα complex,[9] which is involved in base mismatch repair and short insertion/deletion loops.[10] MSH2 heterodimerization stabilizes MSH6, which is not stable because of its N-terminal disordered domain. Conversely, MSH2 does not have a nuclear localization sequence (NLS), so it is believed that MSH2 and MSH6 dimerize in the cytoplasm and then are imported into the nucleus together.[11] In the MutSα dimer, MSH6 interacts with the DNA for mismatch recognition while MSH2 provides the stability that MSH6 requires. MSH2 can be imported into the nucleus without dimerizing to MSH6, in this case, MSH2 is probably dimerized to MSH3 to form MutSβ.[12] MSH2 has two interacting domains with MSH6 in the MutSα heterodimer, a DNA interacting domain, and an ATPase domain.[13]
The MutSα dimer scans double stranded DNA in the nucleus, looking for mismatched bases. When the complex finds one, it repairs the mutation in an ATP dependent manner. The MSH2 domain of MutSα prefers ADP to ATP, with the MSH6 domain preferring the opposite. Studies have indicated that MutSα only scans DNA with the MSH2 domain harboring ADP, while the MSH6 domain can contain either ADP or ATP.[14] MutSα then associates with MutL to repair the damaged DNA.
MutSβ is formed when MSH2 complexes with MSH3 instead of MSH6. This dimer repairs longer insertion/deletion loops than MutSα.[15] Because of the nature of the mutations that this complex repairs, this is probably the state of MSH2 that causes the microsatellite instability phenotype. Large DNA insertions and deletions intrinsically bend the DNA double helix. The MSH2/MSH3 dimer can recognize this topology and initiate repair. The mechanism by which it recognizes mutations is different as well, because it separates the two DNA strands, which MutSα does not.[16]
References
[edit]- ^ Mellon, Isabel; Rajpal, Deepak K.; Koi, Minoru; Boland, C. Richard; Champe, Gregory N. (26). "Transcription-Coupled Repair Deficiency and Mutations in Human Mismatch Repair Genes". Science. 26 (5261): 557–560. doi:10.1126/science.272.5261.557. PMID 8614807.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|month=ignored (help) - ^ De Wind, Niels; Dekker, Marleen; Berns, Anton; Radman, Miroslav; Te Riele, Hein (28). "Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer". Cell. 82 (2): 321–330. doi:10.1016/0092-8674(95)90319-4. PMID 7628020.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|month=ignored (help) - ^ Pitsikas, P.; Lee, D.; Rainbow, A. J. (9). "Reduced host cell reactivation of oxidative DNA damage in human cells deficient in the mismatch repair gene hMSH2". Mutagenesis. 22 (3): 235–243. doi:10.1093/mutage/gem008. PMID 17351251.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|month=ignored (help) - ^ Müller, A.; Fishel, R. (2002). "Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC)". Cancer Invest. 20 (1): 102–109. doi:10.1081/cnv-120000371. PMID 11852992.
{{cite journal}}: CS1 maint: date and year (link) - ^ Warren, Joshua J.; Pohlhaus, Timothy J.; Changela, Anita; Iyer, Ravi R.; Modrich, Paul L.; Beese, Lorena S. (2). "Structure of the Human MutSα DNA Lesion recogniion Complex". Molecular Cell. 26 (4): 579–592. doi:10.1016/j.molcel.2007.04.018. PMID 17531815.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|month=ignored (help) - ^ Bonis, P. A.; Trikalinos, T. A.; Chung, M.; Chew, P.; Ip, S.; Devine, D. A.; Lau, J. (2007). "Hereditary nonpolyposis colorectal cancer: diagnostic strategies and their implications". Evidence Reports/Technology Assessments. 150 (150): 1–180. PMC 4781224. PMID 17764220.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: date and year (link) - ^ Zhang, Xuchen; Li, Jia (15). "Era of universal testing of microsatellite instability in colorectal cancer". World J Gastrointest Oncol. 5 (2): 12–19. doi:10.4251/wjgo.v5.i2.12. PMC 3613766. PMID 23556052.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|month=ignored (help)CS1 maint: unflagged free DOI (link) - ^ Scherer, Stefan J. (14). "JOBNAME: BBRC 221#3 PAGE: 1 SESS: 24 OUTPUT: Wed May 29 06:34:46 1996 /Specific in Vitro Binding of p53 to the Promoter Region of the Human Mismatch Repair Gene hMSH2". Biochemical and Biophysical Reasearch Communications. 221 (3): 722–728. doi:10.1006/bbrc.1996.0663. PMID 8630028.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ Hargreaves, Victoria V.; Shell, Scarlet S.; Mazur, Dan J.; Hess, Martin T.; Kolodner, Richard D. (20 January 2010). "Interaction between the Msh2 and Msh6 Nucleotide-binding Sites in the Saccharomyces cerevisiae Msh2-Msh6 Complex". Journal of Biological Chemistry. 285 (12): 9301–9310. doi:10.1074/jbc.M109.096388. PMID 20089866.
{{cite journal}}: CS1 maint: date and year (link) - ^ Drummond, James T.; Li, Guo-Min; Longley, Matthew J.; Modrich, Paul (30). "Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells". Science. 268 (5219): 1909–1912. doi:10.1126/science.7604264. PMID 7604264.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|month=ignored (help) - ^ Christmann, M.; Kaina, B. (17). "Nuclear Translocation of Mismatch Repair Proteins MSH2 and MSH6 as a Response of Cells to Alkylating Agents". J. Biol. Chem. 275 (46): 36256–36262. doi:10.1074/jbc.Moo5377200 (inactive 2023-08-02). PMID 10954713.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|month=ignored (help)CS1 maint: DOI inactive as of August 2023 (link) CS1 maint: unflagged free DOI (link) - ^ Edelbrock, Michael A.; Kaliyaperumal, Saravanan; Williams, Kandace J. (4). "Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other non-canonical activities". Mutat. Res.: Fundam. Mol. Mech. Mutagen. 743–744: 53–66. doi:10.1016/j.mrfmmm.2012.12.008. PMC 3659183. PMID 23391514.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|month=ignored (help) - ^ Guerrette, S.; Wilson, T.; Gradia, S.; Fishel, R. (1998). "Interactions of Human hMSH3 and hMSH2 with hMSH6:Examination of Mutations Found in Hereditary Nonpolyposis Colorectal Cancer". Molecular and Cellular Biology. 18 (11): 6616–6623. doi:10.1128/MCB.18.11.6616. PMC 109246. PMID 9774676.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: date and year (link) - ^ Qiu, Ruoyi; Derocco, Vanessa C.; Harris, Credle; Sharma, Anushi; Hingorani, Manju M.; Erie, Dorothy A.; Weninger, Keith R. (2012). "Large conformational changes in MutS during DNA scanning, mismatch recognition and repair signalling". EMBO J. 31 (11): 2528–2540. doi:10.1038/emboj.2012.95. PMC 3365432. PMID 22505031.
{{cite journal}}: CS1 maint: date and year (link) - ^ Dowen, Jill M.; Putnam, Christopher D.; Kolodner, Richard D. (26). "Functional Studies and Homology Modeling of MSH2-MSH3 Predict that Mispair Recognition Involves DNA Bending and Strand Seperation". Mol. Cell. Biol. 30 (13): 3321–3328. doi:10.1128/MCB.01558-09. PMC 2897569. PMID 20421420.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|month=ignored (help) - ^ Gupta, Shikha; Gellert, Martin; Yang, Wei (18). "Mechanism of mismatch recognition revealed by human MutSβ bound to unpaired DNA loops". Na. Struct. Mol. Biol. 19 (1): 72–78. doi:10.1038/nsmb.2175. PMID PMC3252464.
{{cite journal}}: Check|pmid=value (help); Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|month=ignored (help)