muts homolog 2 protein

Summary

Summary: A highly conserved eukaryotic homolog of the MUTS DNA MISMATCH-BINDING PROTEIN. It plays an essential role in meiotic RECOMBINATION and DNA REPAIR of mismatched NUCLEOTIDES.

Top Publications

  1. Martin S, McCabe N, Mullarkey M, Cummins R, Burgess D, Nakabeppu Y, et al. DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1. Cancer Cell. 2010;17:235-48 pubmed publisher
    ..These data suggest targeted, mechanism-based therapeutic approaches. ..
  2. Kantelinen J, Kansikas M, Korhonen M, Ollila S, Heinimann K, Kariola R, et al. MutSbeta exceeds MutSalpha in dinucleotide loop repair. Br J Cancer. 2010;102:1068-73 pubmed publisher
    ..The finding is clinically relevant because the strong role of MutSbeta in IDL2 repair indicates MSH3 deficiency in tumours with low dinucleotide and no mononucleotide repeat instability. ..
  3. Arlow T, Scott K, Wagenseller A, Gammie A. Proteasome inhibition rescues clinically significant unstable variants of the mismatch repair protein Msh2. Proc Natl Acad Sci U S A. 2013;110:246-51 pubmed publisher
    ..Our results provide the foundation for an innovative therapeutic regime for certain mismatch-repair-defective cancers that are refractory to conventional chemotherapies. ..
  4. Win A, Lindor N, Young J, Macrae F, Young G, Williamson E, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012;104:1363-72 pubmed
    ..We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers...
  5. Hombauer H, Campbell C, Smith C, Desai A, Kolodner R. Visualization of eukaryotic DNA mismatch repair reveals distinct recognition and repair intermediates. Cell. 2011;147:1040-53 pubmed publisher
    ..These findings suggest the presence of replication machinery-coupled and -independent pathways for mispair recognition by Msh2-Msh6, which direct formation of superstoichiometric Mlh1-Pms1 foci that represent sites of active MMR. ..
  6. Zlatanou A, Despras E, Braz Petta T, Boubakour Azzouz I, Pouvelle C, Stewart G, et al. The hMsh2-hMsh6 complex acts in concert with monoubiquitinated PCNA and Pol ? in response to oxidative DNA damage in human cells. Mol Cell. 2011;43:649-62 pubmed publisher
  7. Javaid S, Manohar M, Punja N, Mooney A, Ottesen J, Poirier M, et al. Nucleosome remodeling by hMSH2-hMSH6. Mol Cell. 2009;36:1086-94 pubmed publisher
  8. Langeberg W, Kwon E, Koopmeiners J, Ostrander E, Stanford J. Population-based study of the association of variants in mismatch repair genes with prostate cancer risk and outcomes. Cancer Epidemiol Biomarkers Prev. 2010;19:258-64 pubmed publisher
  9. Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304-10 pubmed publisher
    ..Lifetime ovarian and endometrial cancer risks associated with MLH1 or MSH2 mutations were high but do not increase appreciably until after the age of 40 years. ..

More Information

Publications62

  1. Mastrocola A, Heinen C. Nuclear reorganization of DNA mismatch repair proteins in response to DNA damage. DNA Repair (Amst). 2010;9:120-33 pubmed publisher
    ..In contrast, hMLH1 is excluded from the nucleolus at all times. Thus, the nucleolus may act to segregate a population of hMSH2-hMSH6 from hMLH1-hPMS2 such that, in the absence of DNA damage, an inappropriate response is not invoked. ..
  2. Valeri N, Gasparini P, Fabbri M, Braconi C, Veronese A, Lovat F, et al. Modulation of mismatch repair and genomic stability by miR-155. Proc Natl Acad Sci U S A. 2010;107:6982-7 pubmed publisher
    ..Finally, a number of MSI tumors with unknown cause of MMR inactivation displayed miR-155 overexpression. These data provide support for miR-155 modulation of MMR as a mechanism of cancer pathogenesis. ..
  3. Forties R, North J, Javaid S, Tabbaa O, Fishel R, Poirier M, et al. A quantitative model of nucleosome dynamics. Nucleic Acids Res. 2011;39:8306-13 pubmed publisher
    ..This model's precise agreement with current experiments suggests that it can be applied more generally to provide important mechanistic understanding of the numerous nucleosome alterations that occur during DNA processing. ..
  4. Green B, Belcheva A, Nepal R, Boulianne B, Martin A. The mismatch repair pathway functions normally at a non-AID target in germinal center B cells. Blood. 2011;118:3013-8 pubmed publisher
    ..These results show that in GC B cells, (1) MMR functions normally at an AID-insensitive gene and (2) the frequency of background mutagenesis is greater in GC B cells than in their precursor follicular B cells...
  5. Buerki N, Gautier L, Kovac M, Marra G, Buser M, Mueller H, et al. Evidence for breast cancer as an integral part of Lynch syndrome. Genes Chromosomes Cancer. 2012;51:83-91 pubmed publisher
    ..7%) of 22 breast cancer specimens from MLH1/MSH2 mutation carriers. These findings, thus, provide strong molecular evidence for a pivotal role of MMR deficiency in breast cancer development in Lynch syndrome. ..
  6. Wielders E, Dekker R, Holt I, Morris G, te Riele H. Characterization of MSH2 variants by endogenous gene modification in mouse embryonic stem cells. Hum Mutat. 2011;32:389-96 pubmed publisher
    ..We have also shown that oligonucleotide-directed gene modification provides a straightforward approach to recreate allelic variants in the endogenous gene in murine ESC. This approach can be extended to other hereditary conditions. ..
  7. Drost M, Zonneveld J, van Hees S, Rasmussen L, Hofstra R, de Wind N. A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants. Hum Mutat. 2012;33:488-94 pubmed publisher
    ..We anticipate that this assay will be an important tool in the development of a comprehensive and widely applicable diagnostic procedure for LS-associated VUS. ..
  8. Bouzourene H, Hutter P, Losi L, Martin P, Benhattar J. Selection of patients with germline MLH1 mutated Lynch syndrome by determination of MLH1 methylation and BRAF mutation. Fam Cancer. 2010;9:167-72 pubmed publisher
    ..These potentially Lynch syndrome patients should be offered genetic counselling before searching for MLH1 gene mutations. ..
  9. Ali H, Olatubosun A, Vihinen M. Classification of mismatch repair gene missense variants with PON-MMR. Hum Mutat. 2012;33:642-50 pubmed publisher
    ..The results can be used, for example, to prioritize cases for experimental studies and assist in the classification of cases. ..
  10. Win A, Young J, Lindor N, Tucker K, Ahnen D, Young G, et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012;30:958-64 pubmed publisher
  11. Win A, Lindor N, Winship I, Tucker K, Buchanan D, Young J, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst. 2013;105:274-9 pubmed publisher
    ..We estimated cancer risks following an endometrial cancer diagnosis for women carrying MMR gene mutations...
  12. Valeri N, Gasparini P, Braconi C, Paone A, Lovat F, Fabbri M, et al. MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2). Proc Natl Acad Sci U S A. 2010;107:21098-103 pubmed publisher
    ..These studies suggest that the down-regulation of the MMR mutator gene associated with miR-21 overexpression may be an important clinical indicator of therapeutic efficacy in colorectal cancer. ..
  13. Ketabi Z, Bartuma K, Bernstein I, Malander S, Gronberg H, Björck E, et al. Ovarian cancer linked to Lynch syndrome typically presents as early-onset, non-serous epithelial tumors. Gynecol Oncol. 2011;121:462-5 pubmed publisher
  14. Martin S, Hewish M, Sims D, Lord C, Ashworth A. Parallel high-throughput RNA interference screens identify PINK1 as a potential therapeutic target for the treatment of DNA mismatch repair-deficient cancers. Cancer Res. 2011;71:1836-48 pubmed publisher
    ..Therefore, PINK1 represents a potential therapeutic target for the treatment of cancers characterized by MMR deficiency caused by a range of different gene deficiencies. ..
  15. Souza L, Fonseca Silva T, Pereira C, Santos E, Lima L, Carvalho H, et al. Immunohistochemical analysis of p53, APE1, hMSH2 and ERCC1 proteins in actinic cheilitis and lip squamous cell carcinoma. Histopathology. 2011;58:352-60 pubmed publisher
    ..Our data showed that epithelial cells from premalignant to malignant lip disease exhibited changes in the expression of p53, APE1, hMSH2 and ERCC1 proteins; these molecular change might contribute to lip carcinogenesis. ..
  16. van der Post R, Kiemeney L, Ligtenberg M, Witjes J, Hulsbergen van de Kaa C, Bodmer D, et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet. 2010;47:464-70 pubmed publisher
    ..Patients with Lynch syndrome carrying an MSH2 mutation are at increased risk of urinary tract cancer including bladder cancer. In these cases surveillance should be considered. ..
  17. Ohrling K, Edler D, Hallström M, Ragnhammar P. Mismatch repair protein expression is an independent prognostic factor in sporadic colorectal cancer. Acta Oncol. 2010;49:797-804 pubmed publisher
    ..Conclusion. This study reveals that IHC of MLH1 and MSH2 expression can yield important prognostic information but is not a predictive factor for adjuvant 5-FU-based chemotherapy in sporadic CRC. ..
  18. Mendez Bermudez A, Royle N. Deficiency in DNA mismatch repair increases the rate of telomere shortening in normal human cells. Hum Mutat. 2011;32:939-46 pubmed publisher
    ..This is the first demonstration that MSH2 deficiency alone can lead to accelerated telomere shortening in normal human cells. ..
  19. Shih K, Garg K, Levine D, Kauff N, Abu Rustum N, Soslow R, et al. Clinicopathologic significance of DNA mismatch repair protein defects and endometrial cancer in women 40years of age and younger. Gynecol Oncol. 2011;123:88-94 pubmed publisher
    ..These results may have implications when young women diagnosed with endometrial cancer are counseled regarding prognosis. ..
  20. Geng H, Sakato M, DEROCCO V, Yamane K, Du C, Erie D, et al. Biochemical analysis of the human mismatch repair proteins hMutS? MSH2(G674A)-MSH6 and MSH2-MSH6(T1219D). J Biol Chem. 2012;287:9777-91 pubmed publisher
    ..Implications of these findings for MMR and DNA damage signaling by MMR proteins are discussed. ..
  21. Li D, Hu F, Wang F, Cui B, Dong X, Zhang W, et al. Prevalence of pathological germline mutations of hMLH1 and hMSH2 genes in colorectal cancer. PLoS ONE. 2013;8:e51240 pubmed publisher
  22. Lang W, Coats J, Majka J, Hura G, Lin Y, Rasnik I, et al. Conformational trapping of mismatch recognition complex MSH2/MSH3 on repair-resistant DNA loops. Proc Natl Acad Sci U S A. 2011;108:E837-44 pubmed publisher
    ..We envision that junction dynamics is an active participant and a conformational regulator of repair signaling, and governs whether a loop is removed by MSH2/MSH3 or escapes to become a precursor for mutation. ..
  23. Zhang X, Lv L, Chen Q, Yuan F, Zhang T, Yang Y, et al. Mouse DNA polymerase kappa has a functional role in the repair of DNA strand breaks. DNA Repair (Amst). 2013;12:377-88 pubmed publisher
    ..We speculate that Pol? may have an important role in strand break repair following oxidative stress in vivo. ..
  24. Kuiper R, Vissers L, Venkatachalam R, Bodmer D, Hoenselaar E, Goossens M, et al. Recurrence and variability of germline EPCAM deletions in Lynch syndrome. Hum Mutat. 2011;32:407-14 pubmed publisher
    ..We conclude that 3' end EPCAM deletions are a recurrent cause of Lynch syndrome, which should be implemented in routine Lynch syndrome diagnostics. ..
  25. Kansikas M, Kariola R, Nyström M. Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants. Hum Mutat. 2011;32:107-15 pubmed publisher
    ..In conclusion, taking into consideration the susceptibility gene the three-step model can be utilized in an appropriate and efficient manner to determine the pathogenicity of MMR gene variations. ..
  26. Pastrello C, Pin E, Marroni F, Bedin C, Fornasarig M, Tibiletti M, et al. Integrated analysis of unclassified variants in mismatch repair genes. Genet Med. 2011;13:115-24 pubmed publisher
  27. Cooley N, Elder R, Povey A. The effect of Msh2 knockdown on methylating agent induced toxicity in DNA glycosylase deficient cells. Toxicology. 2010;268:111-7 pubmed publisher
  28. Wei W, Liu L, Chen J, Jin K, Jiang F, Liu F, et al. Racial differences in MLH1 and MSH2 mutation: an analysis of yellow race and white race based on the InSiGHT database. J Bioinform Comput Biol. 2010;8 Suppl 1:111-25 pubmed
    ..1758dupC) in MLH1 and two mutations (c.1255C > A and c.1886A > G) in MSH2 were only found in yellow race, which implies that specific mutations in yellow race need more attention when screening mutations in these two genes. ..
  29. Ezzatizadeh V, Pinto R, Sandi C, Sandi M, Al Mahdawi S, te Riele H, et al. The mismatch repair system protects against intergenerational GAA repeat instability in a Friedreich ataxia mouse model. Neurobiol Dis. 2012;46:165-71 pubmed publisher
    ..These findings reveal substantial differences in the intergenerational dynamics of expanded GAA repeat sequences compared with expanded CAG/CTG repeats, where Msh2 and Msh3 are thought to actively promote repeat expansions. ..
  30. Pettersen H, Visnes T, Vågbø C, Svaasand E, Doseth B, Slupphaug G, et al. UNG-initiated base excision repair is the major repair route for 5-fluorouracil in DNA, but 5-fluorouracil cytotoxicity depends mainly on RNA incorporation. Nucleic Acids Res. 2011;39:8430-44 pubmed publisher
    ..In conclusion, UNG-initiated BER is the major route for FU-DNA repair, but cytotoxicity of FU is predominantly RNA-mediated, while DNA-mediated effects are limited to FdUrd. ..
  31. Engel C, Loeffler M, Steinke V, Rahner N, Holinski Feder E, Dietmaier W, et al. Risks of less common cancers in proven mutation carriers with lynch syndrome. J Clin Oncol. 2012;30:4409-15 pubmed publisher
    ..The sex- and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome. ..
  32. Martin S, McCarthy A, Barber L, Burgess D, Parry S, Lord C, et al. Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2. EMBO Mol Med. 2009;1:323-37 pubmed publisher
    ..While methotrexate has been used for many years as a cancer therapy, our observations suggest that this drug may have particular utility for the treatment of a subset of patients with tumours characterized by MSH2 mutations. ..
  33. Martinez S, Kolodner R. Functional analysis of human mismatch repair gene mutations identifies weak alleles and polymorphisms capable of polygenic interactions. Proc Natl Acad Sci U S A. 2010;107:5070-5 pubmed publisher
    ..These results indicate that weak MMR gene alleles capable of polygenic interactions with other MMR gene alleles may be relatively common. ..
  34. Dowen J, Putnam C, Kolodner R. Functional studies and homology modeling of Msh2-Msh3 predict that mispair recognition involves DNA bending and strand separation. Mol Cell Biol. 2010;30:3321-8 pubmed publisher
    ..Mapping of the two classes of mutations onto the Msh3 MBD model appears to distinguish mispair recognition regions from DNA stabilization regions. ..
  35. Williams S, Wilson J, Clark A, Mitson Salazar A, Tomashevski A, Ananth S, et al. Functional and physical interaction between the mismatch repair and FA-BRCA pathways. Hum Mol Genet. 2011;20:4395-410 pubmed publisher
    ..These results suggest a significant role for MMR proteins in the activation of the FA pathway and repair of ICLs. In addition, we provide the first evidence for a defect in MMR in FA cell lines. ..
  36. Arnason T, Sapp H, Rayson D, Barnes P, Drewniak M, Nassar B, et al. Loss of expression of DNA mismatch repair proteins is rare in pancreatic and small intestinal neuroendocrine tumors. Arch Pathol Lab Med. 2011;135:1539-44 pubmed publisher
    ..The remainder had intact MMR protein expression. Defects in DNA MMR proteins are rare in pancreatic and small intestinal NETs, raising doubt that MSI plays a significant role in the pathogenesis of these tumors. ..
  37. Stoffel E, Mukherjee B, Raymond V, Tayob N, Kastrinos F, Sparr J, et al. Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology. 2009;137:1621-7 pubmed publisher
    ..76%-80.54%). Lifetime risks of CRC and EC in mismatch repair gene mutation carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized cancer surveillance is necessary. ..
  38. Lynch H, Casey M, Snyder C, Bewtra C, Lynch J, Butts M, et al. Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management. Mol Oncol. 2009;3:97-137 pubmed publisher
    ..This paper reviews the subject of hereditary ovarian cancer, with particular attention to its molecular genetic basis, its pathology, and its phenotypic/genotypic heterogeneity. ..
  39. Topping R, Wilkinson J, Scarpinato K. Mismatch repair protein deficiency compromises cisplatin-induced apoptotic signaling. J Biol Chem. 2009;284:14029-39 pubmed publisher
  40. Lützen A, de Wind N, Georgijevic D, Nielsen F, Rasmussen L. Functional analysis of HNPCC-related missense mutations in MSH2. Mutat Res. 2008;645:44-55 pubmed publisher
    ..In conclusion, all mutant proteins (except for MSH2-A305T) have defects; either in mismatch binding, ATP-release, mismatch repair activity, subcellular localization or protein-protein interactions. ..
  41. Jin H, Liu X, Li V, Ding Y, Yang B, Geng J, et al. Detection of mismatch repair gene germline mutation carrier among Chinese population with colorectal cancer. BMC Cancer. 2008;8:44 pubmed publisher
    ..Application of NCI recommended criteria may not be effective enough to identify Chinese HNPCC families. Further studies are necessary to echo or refute our results so as to make the NCI recommendation more universally applicable. ..
  42. Barnetson R, Cartwright N, van Vliet A, Haq N, Drew K, Farrington S, et al. Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer. Hum Mutat. 2008;29:367-74 pubmed
    ..V716M, and MSH2 c.965G>A p.G322D). These findings support a causal link with colorectal cancer for several DNA mismatch repair gene variants. However, the majority of missense changes are likely to be inconsequential polymorphisms. ..
  43. Christensen L, Madsen B, Wikman F, Wiuf C, Koed K, Tjønneland A, et al. The association between genetic variants in hMLH1 and hMSH2 and the development of sporadic colorectal cancer in the Danish population. BMC Med Genet. 2008;9:52 pubmed publisher
    ..Nevertheless, some of the rare unclassified variants in hMLH1 and hMSH2 might be involved in the development of colorectal cancer in the families where they were originally identified. ..
  44. Gylling A, Nieminen T, Abdel Rahman W, Nuorva K, Juhola M, Joensuu E, et al. Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors. Carcinogenesis. 2008;29:1351-9 pubmed publisher
    ..Uroepithelial cancers of the ureter (and bladder to lesser extent) share many characteristics of MMR deficiency-driven tumorigenesis, whereas brain tumors and kidney adenocarcinomas follow separate pathways...
  45. Dragileva E, Hendricks A, Teed A, Gillis T, Lopez E, Friedberg E, et al. Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes. Neurobiol Dis. 2009;33:37-47 pubmed publisher
  46. Kouso H, Yoshino I, Miura N, Takenaka T, Ohba T, Yohena T, et al. Expression of mismatch repair proteins, hMLH1/hMSH2, in non-small cell lung cancer tissues and its clinical significance. J Surg Oncol. 2008;98:377-83 pubmed publisher
    ..The genetic instability is possibly due to the reduced expression of hMLH1 protein, and hMSH2 expression is associated with smoking status. ..
  47. Bujalkova M, Zavodna K, Krivulcik T, Ilencikova D, Wolf B, Kovac M, et al. Multiplex SNaPshot genotyping for detecting loss of heterozygosity in the mismatch-repair genes MLH1 and MSH2 in microsatellite-unstable tumors. Clin Chem. 2008;54:1844-54 pubmed publisher
    ..We developed a simple, low-cost method based on single-nucleotide polymorphism (SNP) genotyping and capillary electrophoresis for the assessment of LOH at 2 MMR loci simultaneously...
  48. Fan Y, Liu X, Zhang H, Dai J, Zhang X, Zhu M, et al. Variations in exon 7 of the MSH2 gene and susceptibility to gastrointestinal cancer in a Chinese population. Cancer Genet Cytogenet. 2006;170:121-8 pubmed
    ..1223A>G (p.Tyr408Cys) in MSH2 and c.655 A>G (p.Ile219 Val) and c.927C>T (p.Pro309Pro) in MLH1 might be merely polymorphisms. Consequences of the variant c.2101C>A (p.Gln701Lys) in MLH1 remain to be elucidated. ..
  49. Kovacs M, Papp J, Szentirmay Z, Otto S, Olah E. Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat. 2009;30:197-203 pubmed publisher
    ..Thus, analysis of the 3' region of the TACSTD1 gene should be included in the routine mutation screening protocols for HNPCC...
  50. Lynch P. The hMSH2 and hMLH1 genes in hereditary nonpolyposis colorectal cancer. Surg Oncol Clin N Am. 2009;18:611-24 pubmed publisher
    ..It is not always possible to discuss these specific genes without commenting on the broader problem of HNPCC diagnosis and management. ..
  51. Zighelboim I, Goodfellow P, Gao F, Gibb R, Powell M, Rader J, et al. Microsatellite instability and epigenetic inactivation of MLH1 and outcome of patients with endometrial carcinomas of the endometrioid type. J Clin Oncol. 2007;25:2042-8 pubmed
    ..95; 95% CI, 0.62 to 1.46; P = .82) or DFS (MSI+/MLH1-U: HR, 0.51; 95% CI, 0.22 to 1.19; P = .12; MSI+/MLH1-M: HR, 0.93; 95% CI, 0.62 to 1.40; P = .72). MSI is not associated with survival in patients with endometrioid endometrial cancer. ..
  52. Maguire K, Kmiec E. Multiple roles for MSH2 in the repair of a deletion mutation directed by modified single-stranded oligonucleotides. Gene. 2007;386:107-14 pubmed
    ..These results reveal that the mechanism of TNE between yeast and mammalian cells is not conserved, and demonstrate that the suppression of the TNE reaction can be bypassed using RNAi against MSH2 designed to knockdown its expression. ..
  53. Sheng J, Chan T, Chan Y, Huang J, Chen J, Zhang M, et al. Microsatellite instability and novel mismatch repair gene mutations in northern Chinese population with hereditary non-polyposis colorectal cancer. Chin J Dig Dis. 2006;7:197-205 pubmed