MSH2 — Mediated Wiki

{{Short description|Protein-coding gene in the species Homo sapiens}} {{Use dmy dates|date=April 2016}} {{Infobox gene}} '''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]],<ref name=Mellon>{{cite journal |vauthors=Mellon I, Rajpal DK, Koi M, Boland CR, Champe GN | title = Transcription-coupled repair deficiency and mutations in human mismatch repair genes | journal = Science | volume = 272 | issue = 5261 | pages = 557–60 |date=April 1996 | pmid = 8614807 | doi = 10.1126/science.272.5261.557 | bibcode = 1996Sci...272..557M | s2cid = 13084965 | url = https://zenodo.org/record/1231074 }}</ref> [[homologous recombination]],<ref name=Wind>{{cite journal |vauthors=de Wind N, Dekker M, Berns A, Radman M, te Riele H | title = Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer | journal = Cell | volume = 82 | issue = 2 | pages = 321–30 |date=July 1995 | pmid = 7628020 | doi = 10.1016/0092-8674(95)90319-4 | s2cid = 7954019 | doi-access = free }}</ref> and [[base excision repair]].<ref name=Pitsikas>{{cite journal |vauthors=Pitsikas P, Lee D, Rainbow AJ | title = Reduced host cell reactivation of oxidative DNA damage in human cells deficient in the mismatch repair gene hMSH2 | journal = Mutagenesis | volume = 22 | issue = 3 | pages = 235–43 |date=May 2007 | pmid = 17351251 | doi = 10.1093/mutage/gem008 | doi-access = free }}</ref>

Mutations in the MSH2 gene are associated with [[microsatellite instability]] and some cancers, especially with [[hereditary nonpolyposis colorectal cancer]] (HNPCC). At least 114 disease-causing mutations in this gene have been discovered.<ref name = "Šimčíková_2019 - supplementary table S7">{{cite journal | vauthors = Šimčíková D, Heneberg P | title = Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases | journal = Scientific Reports | volume = 9 | issue = 1 | article-number = 18577 | date = December 2019 | pmid = 31819097 | pmc = 6901466 | doi = 10.1038/s41598-019-54976-4| bibcode = 2019NatSR...918577S }}</ref>

== Clinical significance ==

[[Hereditary nonpolyposis colorectal cancer]] (HNPCC), 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 MLH1 mutations.<ref name="pmid11852992">{{cite journal |vauthors=Müller A, Fishel R | title = Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC) | journal = Cancer Invest. | volume = 20 | issue = 1 | pages = 102–9 | year = 2002 | pmid = 11852992 | doi = 10.1081/cnv-120000371| s2cid = 3581304 }}</ref> 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]], [[Chemical stability|stability]], [[allosteric regulation]], MSH2-MSH6 interface, and [[DNA-binding domain|DNA binding]].<ref name="pmid17531815">{{cite journal |vauthors=Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS | title = Structure of the human MutSalpha DNA lesion recognition complex | journal = Mol. Cell | volume = 26 | issue = 4 | pages = 579–92 |date=May 2007 | pmid = 17531815 | doi = 10.1016/j.molcel.2007.04.018 | doi-access = free }}</ref> Mutations in MSH2 and other mismatch repair genes cause DNA damage to go unrepaired, resulting in an increase in mutation frequency. These mutations build up over a person's life that otherwise would not have occurred had the DNA been repaired properly.

==Microsatellite instability== 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 phenomenon 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.<ref name="pmid17764220">{{cite journal |vauthors=Bonis PA, Trikalinos TA, Chung M, Chew P, Ip S, DeVine DA, Lau J | title = Hereditary nonpolyposis colorectal cancer: diagnostic strategies and their implications | journal = Evid Rep Technol Assess (Full Rep) | issue = 150 | pages = 1–180 |date=May 2007 | pmid = 17764220 | pmc=4781224}}</ref> 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 for MSI starting with either IHC or PCR-based MSI testing is cost effective, sensitive, specific and is generally widely accepted."<ref name="pmid23556052">{{cite journal |vauthors=Zhang X, Li J | title = Era of universal testing of microsatellite instability in colorectal cancer | journal = World J Gastrointest Oncol | volume = 5 | issue = 2 | pages = 12–9 |date=February 2013 | pmid = 23556052 | pmc = 3613766 | doi = 10.4251/wjgo.v5.i2.12 | doi-access = free }}</ref>

== Role in mismatch repair == In eukaryotes from yeast to humans, MSH2 dimerizes with MSH6 to form the MutSα complex,<ref name="pmid20089866">{{cite journal |vauthors=Hargreaves VV, Shell SS, Mazur DJ, Hess MT, Kolodner RD | title = Interaction between the Msh2 and Msh6 nucleotide-binding sites in the Saccharomyces cerevisiae Msh2-Msh6 complex | journal = J. Biol. Chem. | volume = 285 | issue = 12 | pages = 9301–10 |date=March 2010 | pmid = 20089866 | pmc = 2838348 | doi = 10.1074/jbc.M109.096388 | doi-access = free }}</ref> which is involved in base mismatch repair and short insertion/deletion loops.<ref name="pmid7604264">{{cite journal |vauthors=Drummond JT, Li GM, Longley MJ, Modrich P | title = Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells | journal = Science | volume = 268 | issue = 5219 | pages = 1909–12 |date=June 1995 | pmid = 7604264 | doi = 10.1126/science.7604264 | bibcode = 1995Sci...268.1909D }}</ref> MSH2 heterodimerization stabilizes MSH6, which is not stable because of its N-terminal disordered domain. Conversely, MSH2 does not have a nuclear localization sequence ([[Nuclear localization sequence|NLS]]), so it is believed that MSH2 and MSH6 dimerize in the [[cytoplasm]] and then are imported into the [[Cell nucleus|nucleus]] together.<ref name="pmid10954713">{{cite journal |vauthors=Christmann M, Kaina B | title = Nuclear translocation of mismatch repair proteins MSH2 and MSH6 as a response of cells to alkylating agents | journal = J. Biol. Chem. | volume = 275 | issue = 46 | pages = 36256–62 |date=November 2000 | pmid = 10954713 | doi = 10.1074/jbc.M005377200 | doi-access = free }}</ref> 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.<ref name="pmid23391514">{{cite journal |vauthors=Edelbrock MA, Kaliyaperumal S, Williams KJ | title = Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities | journal = Mutat. Res. | volume = 743–744| pages = 53–66|date=February 2013 | pmid = 23391514 | doi = 10.1016/j.mrfmmm.2012.12.008 | pmc=3659183}}</ref> MSH2 has two interacting domains with MSH6 in the MutSα heterodimer, a DNA interacting domain, and an ATPase domain.<ref name="pmid9774676">{{cite journal |vauthors=Guerrette S, Wilson T, Gradia S, Fishel R | title = Interactions of human hMSH2 with hMSH3 and hMSH2 with hMSH6: examination of mutations found in hereditary nonpolyposis colorectal cancer | journal = Mol. Cell. Biol. | volume = 18 | issue = 11 | pages = 6616–23 |date=November 1998 | pmid = 9774676 | pmc = 109246 | doi = 10.1128/mcb.18.11.6616}}</ref>

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 [[Adenosine triphosphate|ATP]] dependent manner. The MSH2 domain of MutSα prefers [[Adenosine diphosphate|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.<ref name="pmid22505031">{{cite journal |vauthors=Qiu R, DeRocco VC, Harris C, Sharma A, Hingorani MM, Erie DA, Weninger KR | title = Large conformational changes in MutS during DNA scanning, mismatch recognition and repair signalling | journal = EMBO J. | volume = 31 | issue = 11 | pages = 2528–40 |date=May 2012 | pmid = 22505031 | doi = 10.1038/emboj.2012.95 | pmc=3365432}}</ref> MutSα then associates with MLH1 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.<ref name="pmid20421420">{{cite journal |vauthors=Dowen JM, Putnam CD, Kolodner RD | title = Functional studies and homology modeling of Msh2-Msh3 predict that mispair recognition involves DNA bending and strand separation | journal = Mol. Cell. Biol. | volume = 30 | issue = 13 | pages = 3321–8 |date=July 2010 | pmid = 20421420 | pmc = 2897569 | doi = 10.1128/MCB.01558-09 }}</ref> 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.<ref name="pmid22179786">{{cite journal |vauthors=Gupta S, Gellert M, Yang W | title = Mechanism of mismatch recognition revealed by human MutSβ bound to unpaired DNA loops | journal = Nat. Struct. Mol. Biol. | volume = 19 | issue = 1 | pages = 72–8 |date=January 2012 | pmid = 22179786 | pmc = 3252464 | doi = 10.1038/nsmb.2175 }}</ref>

==Double-strand break repair== Msh2 modulates accurate [[homologous recombination]], a prominent [[DNA repair|DNA double-strand break repair]] pathway in mammalian [[chromosome]]s.<ref name = Smith2007>{{cite journal |vauthors=Smith JA, Bannister LA, Bhattacharjee V, Wang Y, Waldman BC, Waldman AS |title=Accurate homologous recombination is a prominent double-strand break repair pathway in mammalian chromosomes and is modulated by mismatch repair protein Msh2 |journal=Mol Cell Biol |volume=27 |issue=22 |pages=7816–27 |date=November 2007 |pmid=17846123 |pmc=2169143 |doi=10.1128/MCB.00455-07 }}</ref> Repair of DNA double-strand breaks by accurate homologous recombination predominates over the inaccurate double-strand break repair pathway of "non-homologous end joining" in hamster, mouse and human somatic cells.<ref name = Smith2007/>

==Interactions== MSH2 has been shown to [[Protein–protein interaction|interact]] with: * [[Ataxia telangiectasia and Rad3 related|ATR]],<ref name=pmid14657349/><ref name="pmid11498787">{{cite journal |vauthors=Wang Q, Zhang H, Guerrette S, Chen J, Mazurek A, Wilson T, Slupianek A, Skorski T, Fishel R, Greene MI | title = Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1 | journal = Oncogene | volume = 20 | issue = 34 | pages = 4640–9 |date=August 2001 | pmid = 11498787 | doi = 10.1038/sj.onc.1204625 | doi-access = free }}</ref> * [[BRCA1]],<ref name=pmid10783165/> * [[CHEK2]],<ref name="pmid15647386">{{cite journal |vauthors=Adamson AW, Beardsley DI, Kim WJ, Gao Y, Baskaran R, Brown KD | title = Methylator-induced, mismatch repair-dependent G2 arrest is activated through Chk1 and Chk2 | journal = Mol. Biol. Cell | volume = 16 | issue = 3 | pages = 1513–26 |date=March 2005 | pmid = 15647386 | pmc = 551512 | doi = 10.1091/mbc.E04-02-0089 }}</ref><ref name="pmid12447371">{{cite journal |vauthors=Brown KD, Rathi A, Kamath R, Beardsley DI, Zhan Q, Mannino JL, Baskaran R | title = The mismatch repair system is required for S-phase checkpoint activation | journal = Nat. Genet. | volume = 33 | issue = 1 | pages = 80–4 |date=January 2003 | pmid = 12447371 | doi = 10.1038/ng1052 | s2cid = 20616220 }}</ref> * [[Exonuclease 1|EXO1]],<ref name="pmid10856833">{{cite journal |vauthors=Rasmussen LJ, Rasmussen M, Lee B, Rasmussen AK, Wilson DM, Nielsen FC, Bisgaard HC | title = Identification of factors interacting with hMSH2 in the fetal liver utilizing the yeast two-hybrid system. In vivo interaction through the C-terminal domains of hEXO1 and hMSH2 and comparative expression analysis | journal = Mutat. Res. | volume = 460 | issue = 1 | pages = 41–52 |date=June 2000 | pmid = 10856833 | doi = 10.1016/S0921-8777(00)00012-4 }}</ref><ref name="pmid9788596">{{cite journal |vauthors=Schmutte C, Marinescu RC, Sadoff MM, Guerrette S, Overhauser J, Fishel R | title = Human exonuclease I interacts with the mismatch repair protein hMSH2 | journal = Cancer Res. | volume = 58 | issue = 20 | pages = 4537–42 |date=October 1998 | pmid = 9788596 }}</ref><ref name="pmid11427529">{{cite journal |vauthors=Schmutte C, Sadoff MM, Shim KS, Acharya S, Fishel R | title = The interaction of DNA mismatch repair proteins with human exonuclease I | journal = J. Biol. Chem. | volume = 276 | issue = 35 | pages = 33011–8 |date=August 2001 | pmid = 11427529 | doi = 10.1074/jbc.M102670200 | doi-access = free }}</ref> * [[MAX (gene)|MAX]],<ref name="pmid12584560">{{cite journal |vauthors=Mac Partlin M, Homer E, Robinson H, McCormick CJ, Crouch DH, Durant ST, Matheson EC, Hall AG, Gillespie DA, Brown R | title = Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX | journal = Oncogene | volume = 22 | issue = 6 | pages = 819–25 |date=February 2003 | pmid = 12584560 | doi = 10.1038/sj.onc.1206252 | doi-access = free }}</ref> * [[MSH3]],<ref name="pmid9774676"/><ref name="pmid14657349">{{cite journal |vauthors=Wang Y, Qin J | title = MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 26 | pages = 15387–92 |date=December 2003 | pmid = 14657349 | pmc = 307577 | doi = 10.1073/pnas.2536810100 | bibcode = 2003PNAS..10015387W | doi-access = free }}</ref><ref name="pmid10029069">{{cite journal |vauthors=Bocker T, Barusevicius A, Snowden T, Rasio D, Guerrette S, Robbins D, Schmidt C, Burczak J, Croce CM, Copeland T, Kovatich AJ, Fishel R | title = hMSH5: a human MutS homologue that forms a novel heterodimer with hMSH4 and is expressed during spermatogenesis | journal = Cancer Res. | volume = 59 | issue = 4 | pages = 816–22 |date=February 1999 | pmid = 10029069 }}</ref><ref name="pmid8942985">{{cite journal |vauthors=Acharya S, Wilson T, Gradia S, Kane MF, Guerrette S, Marsischky GT, Kolodner R, Fishel R | title = hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 93 | issue = 24 | pages = 13629–34 |date=November 1996 | pmid = 8942985 | pmc = 19374 | doi = 10.1073/pnas.93.24.13629 | bibcode = 1996PNAS...9313629A | doi-access = free }}</ref> * [[MSH6]],<ref name=pmid9774676/><ref name=pmid14657349/><ref name="pmid10783165">{{cite journal |vauthors=Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J | title = BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures | journal = Genes Dev. | volume = 14 | issue = 8 | pages = 927–39 |date=April 2000 | pmid = 10783165 | pmc = 316544 | doi = 10.1101/gad.14.8.927}}</ref><ref name=pmid10029069/><ref name=pmid8942985/> and * [[p53]].<ref name="pmid8630028">{{cite journal |vauthors=Scherer SJ, Welter C, Zang KD, Dooley S | title = Specific in vitro binding of p53 to the promoter region of the human mismatch repair gene hMSH2 | journal = Biochem. Biophys. Res. Commun. | volume = 221 | issue = 3 | pages = 722–8 |date=April 1996 | pmid = 8630028 | doi = 10.1006/bbrc.1996.0663 }}</ref>

==Epigenetic MSH2 deficiencies in cancer== DNA damage appears to be the primary underlying cause of cancer,<ref name="pmid18403632">{{cite journal | vauthors = Kastan MB | title = DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture | journal = Molecular Cancer Research | volume = 6 | issue = 4 | pages = 517–24 | date = April 2008 | pmid = 18403632 | doi = 10.1158/1541-7786.MCR-08-0020 | doi-access = free }}</ref> and deficiencies in expression of DNA repair genes appear to underlie many forms of cancer.<ref name="pmid18082599">{{cite journal | vauthors = Harper JW, Elledge SJ | title = The DNA damage response: ten years after | journal = Molecular Cell | volume = 28 | issue = 5 | pages = 739–45 | date = December 2007 | pmid = 18082599 | doi = 10.1016/j.molcel.2007.11.015 | doi-access = free }}</ref><ref name="pmid25451105">{{cite journal | vauthors = Dietlein F, Reinhardt HC | title = Molecular pathways: exploiting tumor-specific molecular defects in DNA repair pathways for precision cancer therapy | journal = Clinical Cancer Research | volume = 20 | issue = 23 | pages = 5882–7 | date = December 2014 | pmid = 25451105 | doi = 10.1158/1078-0432.CCR-14-1165 | s2cid = 16005088 | doi-access = }}</ref> If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase [[mutation]]s due to error-prone [[Mutation#Error-prone replication bypass|translesion synthesis]] and error prone repair (see e.g. [[microhomology-mediated end joining]]). Elevated DNA damage may also increase [[Epigenetics|epigenetic]] alterations due to errors during DNA repair.<ref name=Hagan>{{cite journal | vauthors = O'Hagan HM, Mohammad HP, Baylin SB | title = Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island | journal = PLOS Genetics | volume = 4 | issue = 8 | article-number = e1000155 | year = 2008 | pmid = 18704159 | pmc = 2491723 | doi = 10.1371/journal.pgen.1000155 | doi-access = free }}</ref><ref name=Cuozzo>{{cite journal | vauthors = Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV | title = DNA damage, homology-directed repair, and DNA methylation | journal = PLOS Genetics | volume = 3 | issue = 7 | article-number = e110 | date = July 2007 | pmid = 17616978 | pmc = 1913100 | doi = 10.1371/journal.pgen.0030110 | doi-access = free }}{{Retracted|doi=10.1371/journal.pgen.1011921|pmid=41144352|https://retractionwatch.com/2018/12/24/alfredo-fusco-facing-misconduct-charges-in-italy-up-to-21-retractions/ ''Retraction Watch''|doi-access=free}}</ref> Such mutations and epigenetic alterations may give rise to [[cancer]].

Reductions in expression of DNA repair genes (usually caused by epigenetic alterations) are very common in cancers, and are ordinarily much more frequent than mutational defects in DNA repair genes in cancers.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}} (See [[Cancer epigenetics#Frequencies of epimutations in DNA repair genes|Frequencies of epimutations in DNA repair genes]].) In a study of ''MSH2'' in [[Non-small-cell lung carcinoma|non-small cell lung cancer]] (NSCLC), no mutations were found while 29% of NSCLC had epigenetic reduction of ''MSH2'' expression.<ref name=WangYC>{{cite journal |vauthors=Wang YC, Lu YP, Tseng RC, Lin RK, Chang JW, Chen JT, Shih CM, Chen CY |title=Inactivation of hMLH1 and hMSH2 by promoter methylation in primary non-small cell lung tumors and matched sputum samples |journal=J. Clin. Invest. |volume=111 |issue=6 |pages=887–95 |year=2003 |pmid=12639995 |pmc=153761 |doi=10.1172/JCI15475 }}</ref> In [[Acute lymphoblastic leukemia|acute lymphoblastoid leukemia]] (ALL), no MSH2 mutations were found<ref name=Diouf>{{cite journal |vauthors=Diouf B, Cheng Q, Krynetskaia NF, Yang W, Cheok M, Pei D, Fan Y, Cheng C, Krynetskiy EY, Geng H, Chen S, Thierfelder WE, Mullighan CG, Downing JR, Hsieh P, Pui CH, Relling MV, Evans WE |title=Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells |journal=Nat. Med. |volume=17 |issue=10 |pages=1298–303 |year=2011 |pmid=21946537 |pmc=3192247 |doi=10.1038/nm.2430 }}</ref> while 43% of ALL patients showed MSH2 promoter methylation and 86% of relapsed ALL patients had MSH2 promoter methylation.<ref name=WangCX>{{cite journal |vauthors=Wang CX, Wang X, Liu HB, Zhou ZH |title=Aberrant DNA methylation and epigenetic inactivation of hMSH2 decrease overall survival of acute lymphoblastic leukemia patients via modulating cell cycle and apoptosis |journal=Asian Pac. J. Cancer Prev. |volume=15 |issue=1 |pages=355–62 |year=2014 |pmid=24528056 |doi= 10.7314/apjcp.2014.15.1.355|doi-access=free }}</ref> There were, however, mutations in four other genes in ALL patients that destabilized the MSH2 protein, and these were defective in 11% of children with ALL and 16% of adults with this cancer.<ref name=Diouf />

Methylation of the promoter region of the ''MSH2'' gene is correlated with the lack of expression of the MSH2 protein in esophageal cancer,<ref name=Ling2011>{{cite journal |vauthors=Ling ZQ, Li P, Ge MH, Hu FJ, Fang XH, Dong ZM, Mao WM |title=Aberrant methylation of different DNA repair genes demonstrates distinct prognostic value for esophageal cancer |journal=Dig. Dis. Sci. |volume=56 |issue=10 |pages=2992–3004 |year=2011 |pmid=21674174 |doi=10.1007/s10620-011-1774-z |s2cid=22913110 }}</ref> in [[Non-small-cell lung carcinoma|non-small-cell lung cancer]],<ref name=WangYC /><ref name=Hsu>{{cite journal |vauthors=Hsu HS, Wen CK, Tang YA, Lin RK, Li WY, Hsu WH, Wang YC |title=Promoter hypermethylation is the predominant mechanism in hMLH1 and hMSH2 deregulation and is a poor prognostic factor in nonsmoking lung cancer |journal=Clin. Cancer Res. |volume=11 |issue=15 |pages=5410–6 |year=2005 |pmid=16061855 |doi=10.1158/1078-0432.CCR-05-0601 |s2cid=14444548 |doi-access= }}</ref> and in [[colorectal cancer]].<ref name=Lee>{{cite journal |vauthors=Lee KH, Lee JS, Nam JH, Choi C, Lee MC, Park CS, Juhng SW, Lee JH |title=Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence |journal=Langenbecks Arch Surg |volume=396 |issue=7 |pages=1017–26 |year=2011 |pmid=21706233 |doi=10.1007/s00423-011-0812-9 |s2cid=8069716 }}</ref> These correlations suggest that methylation of the promoter region of the ''MSH2'' gene reduces expression of the MSH2 protein. Such promoter methylation would reduce DNA repair in the four pathways in which MSH2 participates: [[DNA mismatch repair]], [[transcription-coupled repair]]<ref name=Mellon /> [[homologous recombination]],<ref name=Wind /><ref name="pmid12810667">{{cite journal |vauthors=Villemure JF, Abaji C, Cousineau I, Belmaaza A |title=MSH2-deficient human cells exhibit a defect in the accurate termination of homology-directed repair of DNA double-strand breaks |journal=Cancer Res. |volume=63 |issue=12 |pages=3334–9 |year=2003 |pmid=12810667 }}</ref><ref name="pmid11283247">{{cite journal |vauthors=Elliott B, Jasin M |title=Repair of double-strand breaks by homologous recombination in mismatch repair-defective mammalian cells |journal=Mol. Cell. Biol. |volume=21 |issue=8 |pages=2671–82 |year=2001 |pmid=11283247 |pmc=86898 |doi=10.1128/MCB.21.8.2671-2682.2001 }}</ref> and [[base excision repair]].<ref name=Pitsikas /> Such reductions in repair likely allow excess DNA damage to accumulate and contribute to [[carcinogenesis]].

The frequencies of ''MSH2'' promoter methylation in several different cancers are indicated in the Table.

{| class="wikitable sortable" |+ ''MSH2'' promoter methylation in sporadic cancers ! Cancer !!Frequency of ''MSH2'' promoter methylation!!{{Reference column heading}} |- ![[Acute lymphoblastic leukemia]]||43%||<ref name=WangCX /> |- !Relapsed [[Acute lymphoblastic leukemia]]||86%||<ref name=WangCX /> |- ![[Renal cell carcinoma]]||51–55%||<ref name="pmid22378480">{{cite journal |vauthors=Stoehr C, Burger M, Stoehr R, Bertz S, Ruemmele P, Hofstaedter F, Denzinger S, Wieland WF, Hartmann A, Walter B |title=Mismatch repair proteins hMLH1 and hMSH2 are differently expressed in the three main subtypes of sporadic renal cell carcinoma |journal=Pathobiology |volume=79 |issue=3 |pages=162–8 |year=2012 |pmid=22378480 |doi=10.1159/000335642 |s2cid=26687941 |url=https://opus4.kobv.de/opus4-fau/files/3401/PAT2012079003162.pdf |doi-access=free }}{{Dead link|date=July 2025 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="pmid25295100">{{cite journal |vauthors=Yoo KH, Won KY, Lim SJ, Park YK, Chang SG |title=Deficiency of MSH2 expression is associated with clear cell renal cell carcinoma |journal=Oncol Lett |volume=8 |issue=5 |pages=2135–2139 |year=2014 |pmid=25295100 |pmc=4186615 |doi=10.3892/ol.2014.2482 }}</ref> |- ![[Esophageal cancer#Squamous-cell carcinoma|Esophageal squamous cell carcinoma]]||29–48%||<ref name=Ling2011 /><ref name="pmid22265839">{{cite journal |vauthors=Ling ZQ, Zhao Q, Zhou SL, Mao WM |title=MSH2 promoter hypermethylation in circulating tumor DNA is a valuable predictor of disease-free survival for patients with esophageal squamous cell carcinoma |journal=Eur J Surg Oncol |volume=38 |issue=4 |pages=326–32 |year=2012 |pmid=22265839 |doi=10.1016/j.ejso.2012.01.008 }}</ref> |- ![[Head and neck squamous-cell carcinoma]]||27–36%||<ref name="pmid17219447">{{cite journal |vauthors=Sengupta S, Chakrabarti S, Roy A, Panda CK, Roychoudhury S |title=Inactivation of human mutL homolog 1 and mutS homolog 2 genes in head and neck squamous cell carcinoma tumors and leukoplakia samples by promoter hypermethylation and its relation with microsatellite instability phenotype |journal=Cancer |volume=109 |issue=4 |pages=703–12 |year=2007 |pmid=17219447 |doi=10.1002/cncr.22430 |s2cid=20191692 |doi-access= }}{{Expression of Concern|doi=10.1002/cncr.35645|pmid=39558863}}</ref><ref name="pmid16569647">{{cite journal |vauthors=Demokan S, Suoglu Y, Demir D, Gozeler M, Dalay N |title=Microsatellite instability and methylation of the DNA mismatch repair genes in head and neck cancer |journal=Ann. Oncol. |volume=17 |issue=6 |pages=995–9 |year=2006 |pmid=16569647 |doi=10.1093/annonc/mdl048 |doi-access=free }}</ref><ref name="pmid19207881">{{cite journal |vauthors=Czerninski R, Krichevsky S, Ashhab Y, Gazit D, Patel V, Ben-Yehuda D |title=Promoter hypermethylation of mismatch repair genes, hMLH1 and hMSH2 in oral squamous cell carcinoma |journal=Oral Dis |volume=15 |issue=3 |pages=206–13 |year=2009 |pmid=19207881 |doi=10.1111/j.1601-0825.2008.01510.x }}</ref> |- ![[Non-small-cell lung carcinoma|Non-small cell lung cancer]]||29–34%||<ref name=WangYC /><ref name=Hsu /> |- ![[Hepatocellular carcinoma]]||10–29%||<ref name="pmid24400091">{{cite journal |vauthors=Hinrichsen I, Kemp M, Peveling-Oberhag J, Passmann S, Plotz G, Zeuzem S, Brieger A |title=Promoter methylation of MLH1, PMS2, MSH2 and p16 is a phenomenon of advanced-stage HCCs |journal=PLOS ONE |volume=9 |issue=1 |article-number=e84453 |year=2014 |pmid=24400091 |pmc=3882222 |doi=10.1371/journal.pone.0084453 |bibcode=2014PLoSO...984453H |doi-access=free }}</ref> |- ![[Colorectal cancer]]||3–24%||<ref name=Lee /><ref name="pmid21766496">{{cite journal |vauthors=Vlaykova T, Mitkova A, Stancheva G, Kadiyska T, Gulubova M, Yovchev Y, Cirovski G, Chilingirov P, Damyanov D, Kremensky I, Mitev V, Kaneva R |title=Microsatellite instability and promoter hypermethylation of MLH1 and MSH2 in patients with sporadic colorectal cancer |journal=J BUON |volume=16 |issue=2 |pages=265–73 |year=2011 |pmid=21766496 }}</ref><ref name="pmid24317816">{{cite journal |vauthors=Malhotra P, Anwar M, Kochhar R, Ahmad S, Vaiphei K, Mahmood S |title=Promoter methylation and immunohistochemical expression of hMLH1 and hMSH2 in sporadic colorectal cancer: a study from India |journal=Tumour Biol. |volume=35 |issue=4 |pages=3679–87 |year=2014 |pmid=24317816 |doi=10.1007/s13277-013-1487-3 |s2cid=10615946 }}</ref><ref name="pmid24052709">{{cite journal |vauthors=Onrat S, Ceken I, Ellidokuz E, Kupelioğlu A |title=Alterations of copy number of methylation pattern in mismatch repair genes by methylation specific-multiplex ligation-dependent probe amplification in cases of colon cancer |journal=Balkan J. Med. Genet. |volume=14 |issue=2 |pages=25–34 |year=2011 |pmid=24052709 |pmc=3776700 |doi=10.2478/v10034-011-0044-x }}</ref> |- ![[Soft-tissue sarcoma]]||8%||<ref name="pmid16258501">{{cite journal |vauthors=Kawaguchi K, Oda Y, Saito T, Yamamoto H, Takahira T, Kobayashi C, Tamiya S, Tateishi N, Iwamoto Y, Tsuneyoshi M |title=DNA hypermethylation status of multiple genes in soft tissue sarcomas |journal=Mod. Pathol. |volume=19 |issue=1 |pages=106–14 |year=2006 |pmid=16258501 |doi=10.1038/modpathol.3800502 |doi-access=free }}</ref> |}

==See also== * [[Mismatch repair#MutS homologs]]

==References== {{reflist|35em}}

==Further reading== {{refbegin|35em}} *{{cite journal | author=Jiricny J |title=Colon cancer and DNA repair: have mismatches met their match? |journal=Trends Genet. |volume=10 |issue= 5 |pages= 164–8 |year= 1994 |pmid= 8036718 |doi=10.1016/0168-9525(94)90093-0 }} *{{cite journal |vauthors=Fishel R, Wilson T |title=MutS homologs in mammalian cells. |journal=Curr. Opin. Genet. Dev. |volume=7 |issue= 1 |pages= 105–13 |year= 1997 |pmid= 9024626 |doi=10.1016/S0959-437X(97)80117-7 }} *{{cite journal | author=Lothe RA |title=Microsatellite instability in human solid tumors. |journal=Molecular Medicine Today |volume=3 |issue= 2 |pages= 61–8 |year= 1997 |pmid= 9060003 |doi=10.1016/S1357-4310(96)10055-1 }} *{{cite journal |vauthors=Peltomäki P, de la Chapelle A |title=Mutations predisposing to hereditary nonpolyposis colorectal cancer. |journal=Adv. Cancer Res. |series=Advances in Cancer Research |volume=71 |pages= 93–119 |year= 1997 |pmid= 9111864 |doi=10.1016/S0065-230X(08)60097-4 |isbn=978-0-12-006671-1 }} *{{cite journal |vauthors=Papadopoulos N, Lindblom A |title=Molecular basis of HNPCC: mutations of MMR genes. |journal=Hum. Mutat. |volume=10 |issue= 2 |pages= 89–99 |year= 1997 |pmid= 9259192 |doi= 10.1002/(SICI)1098-1004(1997)10:2<89::AID-HUMU1>3.0.CO;2-H |s2cid=6799575 }} *{{cite journal |vauthors=Kauh J, Umbreit J |title=Colorectal cancer prevention. |journal=Current Problems in Cancer |volume=28 |issue= 5 |pages= 240–64 |year= 2004 |pmid= 15375803 |doi=10.1016/j.currproblcancer.2004.05.004 }} *{{cite journal |vauthors=Warusavitarne J, Schnitzler M |title=The role of chemotherapy in microsatellite unstable (MSI-H) colorectal cancer. |journal=International Journal of Colorectal Disease |volume=22 |issue= 7 |pages= 739–48 |year= 2007 |pmid= 17109103 |doi= 10.1007/s00384-006-0228-0 |s2cid=6460105 }} *{{cite journal |vauthors=Wei Q, Xu X, Cheng L, etal |title=Simultaneous amplification of four DNA repair genes and beta-actin in human lymphocytes by multiplex reverse transcriptase-PCR. |journal=Cancer Res. |volume=55 |issue= 21 |pages= 5025–9 |year= 1995 |pmid= 7585546 }} *{{cite journal |vauthors=Wilson TM, Ewel A, Duguid JR, etal |title=Differential cellular expression of the human MSH2 repair enzyme in small and large intestine. |journal=Cancer Res. |volume=55 |issue= 22 |pages= 5146–50 |year= 1995 |pmid= 7585562 }} *{{cite journal |vauthors=Drummond JT, Li GM, Longley MJ, Modrich P |title=Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells. |journal=Science |volume=268 |issue= 5219 |pages= 1909–12 |year= 1995 |pmid= 7604264 |doi=10.1126/science.7604264 |bibcode=1995Sci...268.1909D }} *{{cite journal |vauthors=Kolodner RD, Hall NR, Lipford J, etal |title=Structure of the human MSH2 locus and analysis of two Muir-Torre kindreds for msh2 mutations. |journal=Genomics |volume=24 |issue= 3 |pages= 516–26 |year= 1995 |pmid= 7713503 |doi=10.1006/geno.1994.1661 }} *{{cite journal |vauthors=Wijnen J, Vasen H, Khan PM, etal |title=Seven new mutations in hMSH2, an HNPCC gene, identified by denaturing gradient-gel electrophoresis. |journal=Am. J. Hum. Genet. |volume=56 |issue= 5 |pages= 1060–6 |year= 1995 |pmid= 7726159 | pmc=1801472 }} *{{cite journal |vauthors=Mary JL, Bishop T, Kolodner R, etal |title=Mutational analysis of the hMSH2 gene reveals a three base pair deletion in a family predisposed to colorectal cancer development. |journal=Hum. Mol. Genet. |volume=3 |issue= 11 |pages= 2067–9 |year= 1995 |pmid= 7874129 }} *{{cite journal |vauthors=Fishel R, Ewel A, Lescoe MK |title=Purified human MSH2 protein binds to DNA containing mismatched nucleotides. |journal=Cancer Res. |volume=54 |issue= 21 |pages= 5539–42 |year= 1994 |pmid= 7923193 }} *{{cite journal |vauthors=Fishel R, Ewel A, Lee S, etal |title=Binding of mismatched microsatellite DNA sequences by the human MSH2 protein. |journal=Science |volume=266 |issue= 5189 |pages= 1403–5 |year= 1994 |pmid= 7973733 |doi=10.1126/science.7973733 |bibcode=1994Sci...266.1403F }} *{{cite journal |vauthors=Liu B, Parsons RE, Hamilton SR, etal |title=hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. |journal=Cancer Res. |volume=54 |issue= 17 |pages= 4590–4 |year= 1994 |pmid= 8062247 }} *{{cite journal |vauthors=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1–2 |pages= 171–4 |year= 1994 |pmid= 8125298 |doi=10.1016/0378-1119(94)90802-8 }} *{{cite journal |vauthors=Fishel R, Lescoe MK, Rao MR, etal |title=The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. |journal=Cell |volume=77 |issue= 1 |pages= 167–169 |year= 1994 |pmid= 8156592 |doi=10.1016/0092-8674(94)90306-9 |s2cid=45905483 }} *{{cite journal |vauthors=Fishel R, Lescoe MK, Rao MR, etal |title=The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. |journal=Cell |volume=75 |issue= 5 |pages= 1027–38 |year= 1994 |pmid= 8252616 |doi=10.1016/0092-8674(93)90546-3 |s2cid=46235760 |doi-access= }} {{refend}}

==External links== * {{MeshName|MutS+Homolog+2+Protein}}

[[Category:DNA repair]] [[Category:Mutation]] [[Category:Oncogenes]]