MSH2

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MutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli)
Protein MSH2 PDB 2o8b.png
PDB rendering based on 2o8b.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols MSH2 ; COCA1; FCC1; HNPCC; HNPCC1; LCFS2
External IDs OMIM609309 MGI101816 HomoloGene210 GeneCards: MSH2 Gene
RNA expression pattern
PBB GE MSH2 209421 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4436 17685
Ensembl ENSG00000095002 ENSMUSG00000024151
UniProt P43246 P43247
RefSeq (mRNA) NM_000251 NM_008628
RefSeq (protein) NP_000242 NP_032654
Location (UCSC) Chr 2:
47.63 – 47.79 Mb
Chr 17:
87.67 – 87.72 Mb
PubMed search [1] [2]

DNA mismatch repair protein Msh2 also known as MutS protein 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 that is a DNA mismatch repair (MMR) protein 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,[1] homologous recombination,[2] and base excision repair.[3]

Mutations in the MSH2 gene are associated with microsatellite instability and some cancers, especially with hereditary nonpolyposis colorectal cancer (HNPCC).

Clinical significance[edit]

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.[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, allosteric regulation, MSH2-MSH6 interface, and DNA binding.[5] Mutations in MSH2 and other mismatch repair genes cause mutations to build up over a person's life that otherwise would have been fixed when the mutation was made.

Microsatellite instability[edit]

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]

In eukaryotes from yeast to humans, MSH2 dimerizes with MSH6 to form the MutSα complex,[8] which is involved in base mismatch repair and short insertion/deletion loops.[9] 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.[10] 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.[11] MSH2 has two interacting domains with MSH6 in the MutSα heterodimer, a DNA interacting domain, and an ATPase domain.[12]

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.[13] 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.[14] 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.[15]

Interactions[edit]

MSH2 has been shown to interact with:

See also[edit]

References[edit]

  1. ^ Mellon I, Rajpal DK, Koi M, Boland CR, Champe GN (April 1996). "Transcription-coupled repair deficiency and mutations in human mismatch repair genes". Science 272 (5261): 557–60. doi:10.1126/science.272.5261.557. PMID 8614807. 
  2. ^ de Wind N, Dekker M, Berns A, Radman M, te Riele H (July 1995). "Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer". Cell 82 (2): 321–30. doi:10.1016/0092-8674(95)90319-4. PMID 7628020. 
  3. ^ Pitsikas P, Lee D, Rainbow AJ (May 2007). "Reduced host cell reactivation of oxidative DNA damage in human cells deficient in the mismatch repair gene hMSH2". Mutagenesis 22 (3): 235–43. doi:10.1093/mutage/gem008. PMID 17351251. 
  4. ^ Müller A, Fishel R (2002). "Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC)". Cancer Invest. 20 (1): 102–9. doi:10.1081/cnv-120000371. PMID 11852992. 
  5. ^ Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS (May 2007). "Structure of the human MutSalpha DNA lesion recognition complex". Mol. Cell 26 (4): 579–92. doi:10.1016/j.molcel.2007.04.018. PMID 17531815. 
  6. ^ Bonis PA, Trikalinos TA, Chung M, Chew P, Ip S, DeVine DA, Lau J (May 2007). "Hereditary nonpolyposis colorectal cancer: diagnostic strategies and their implications". Evid Rep Technol Assess (Full Rep) (150): 1–180. PMID 17764220. 
  7. ^ Zhang X, Li J (February 2013). "Era of universal testing of microsatellite instability in colorectal cancer". World J Gastrointest Oncol 5 (2): 12–9. doi:10.4251/wjgo.v5.i2.12. PMC 3613766. PMID 23556052. 
  8. ^ Hargreaves VV, Shell SS, Mazur DJ, Hess MT, Kolodner RD (March 2010). "Interaction between the Msh2 and Msh6 nucleotide-binding sites in the Saccharomyces cerevisiae Msh2-Msh6 complex". J. Biol. Chem. 285 (12): 9301–10. doi:10.1074/jbc.M109.096388. PMC 2838348. PMID 20089866. 
  9. ^ Drummond JT, Li GM, Longley MJ, Modrich P (June 1995). "Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells". Science 268 (5219): 1909–12. doi:10.1126/science.7604264. PMID 7604264. 
  10. ^ Christmann M, Kaina B (November 2000). "Nuclear translocation of mismatch repair proteins MSH2 and MSH6 as a response of cells to alkylating agents". J. Biol. Chem. 275 (46): 36256–62. doi:10.1074/jbc.M005377200. PMID 10954713. 
  11. ^ Edelbrock MA, Kaliyaperumal S, Williams KJ (February 2013). "Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities". Mutat. Res. doi:10.1016/j.mrfmmm.2012.12.008. PMID 23391514. 
  12. ^ a b c Guerrette S, Wilson T, Gradia S, Fishel R (November 1998). "Interactions of human hMSH2 with hMSH3 and hMSH2 with hMSH6: examination of mutations found in hereditary nonpolyposis colorectal cancer". Mol. Cell. Biol. 18 (11): 6616–23. PMC 109246. PMID 9774676. 
  13. ^ Qiu R, DeRocco VC, Harris C, Sharma A, Hingorani MM, Erie DA, Weninger KR (May 2012). "Large conformational changes in MutS during DNA scanning, mismatch recognition and repair signalling". EMBO J. 31 (11): 2528–40. doi:10.1038/emboj.2012.95. PMID 22505031. 
  14. ^ Dowen JM, Putnam CD, Kolodner RD (July 2010). "Functional studies and homology modeling of Msh2-Msh3 predict that mispair recognition involves DNA bending and strand separation". Mol. Cell. Biol. 30 (13): 3321–8. doi:10.1128/MCB.01558-09. PMC 2897569. PMID 20421420. 
  15. ^ Gupta S, Gellert M, Yang W (January 2012). "Mechanism of mismatch recognition revealed by human MutSβ bound to unpaired DNA loops". Nat. Struct. Mol. Biol. 19 (1): 72–8. doi:10.1038/nsmb.2175. PMC 3252464. PMID 22179786. 
  16. ^ a b c Wang Y, Qin J (December 2003). "MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation". Proc. Natl. Acad. Sci. U.S.A. 100 (26): 15387–92. doi:10.1073/pnas.2536810100. PMC 307577. PMID 14657349. 
  17. ^ Wang Q, Zhang H, Guerrette S, Chen J, Mazurek A, Wilson T, Slupianek A, Skorski T, Fishel R, Greene MI (August 2001). "Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1". Oncogene 20 (34): 4640–9. doi:10.1038/sj.onc.1204625. PMID 11498787. 
  18. ^ a b Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (April 2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. 14 (8): 927–39. PMC 316544. PMID 10783165. 
  19. ^ Adamson AW, Beardsley DI, Kim WJ, Gao Y, Baskaran R, Brown KD (March 2005). "Methylator-induced, mismatch repair-dependent G2 arrest is activated through Chk1 and Chk2". Mol. Biol. Cell 16 (3): 1513–26. doi:10.1091/mbc.E04-02-0089. PMC 551512. PMID 15647386. 
  20. ^ Brown KD, Rathi A, Kamath R, Beardsley DI, Zhan Q, Mannino JL, Baskaran R (January 2003). "The mismatch repair system is required for S-phase checkpoint activation". Nat. Genet. 33 (1): 80–4. doi:10.1038/ng1052. PMID 12447371. 
  21. ^ Rasmussen LJ, Rasmussen M, Lee B, Rasmussen AK, Wilson DM, Nielsen FC, Bisgaard HC (June 2000). "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". Mutat. Res. 460 (1): 41–52. doi:10.1016/S0921-8777(00)00012-4. PMID 10856833. 
  22. ^ Schmutte C, Marinescu RC, Sadoff MM, Guerrette S, Overhauser J, Fishel R (October 1998). "Human exonuclease I interacts with the mismatch repair protein hMSH2". Cancer Res. 58 (20): 4537–42. PMID 9788596. 
  23. ^ Schmutte C, Sadoff MM, Shim KS, Acharya S, Fishel R (August 2001). "The interaction of DNA mismatch repair proteins with human exonuclease I". J. Biol. Chem. 276 (35): 33011–8. doi:10.1074/jbc.M102670200. PMID 11427529. 
  24. ^ Mac Partlin M, Homer E, Robinson H, McCormick CJ, Crouch DH, Durant ST, Matheson EC, Hall AG, Gillespie DA, Brown R (February 2003). "Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX". Oncogene 22 (6): 819–25. doi:10.1038/sj.onc.1206252. PMID 12584560. 
  25. ^ a b Bocker T, Barusevicius A, Snowden T, Rasio D, Guerrette S, Robbins D, Schmidt C, Burczak J, Croce CM, Copeland T, Kovatich AJ, Fishel R (February 1999). "hMSH5: a human MutS homologue that forms a novel heterodimer with hMSH4 and is expressed during spermatogenesis". Cancer Res. 59 (4): 816–22. PMID 10029069. 
  26. ^ a b Acharya S, Wilson T, Gradia S, Kane MF, Guerrette S, Marsischky GT, Kolodner R, Fishel R (November 1996). "hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6". Proc. Natl. Acad. Sci. U.S.A. 93 (24): 13629–34. doi:10.1073/pnas.93.24.13629. PMC 19374. PMID 8942985. 
  27. ^ Scherer SJ, Welter C, Zang KD, Dooley S (April 1996). "Specific in vitro binding of p53 to the promoter region of the human mismatch repair gene hMSH2". Biochem. Biophys. Res. Commun. 221 (3): 722–8. doi:10.1006/bbrc.1996.0663. PMID 8630028. 

Further reading[edit]

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

External links[edit]