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PMS2  -  PMS2 postmeiotic segregation increased 2...

Homo sapiens

Synonyms: DNA mismatch repair protein PMS2, HNPCC4, H_DJ0042M02.9, Mismatch repair endonuclease PMS2, PMS1 protein homolog 2, ...
 
 
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Disease relevance of PMS2

 

High impact information on PMS2

  • A mismatch-containing DNA segment spanned by two strand breaks is removed by the 5'-to-3' activity of MutSalpha-activated exonuclease I. The probable endonuclease active site has been localized to a PMS2 DQHA(X)(2)E(X)(4)E motif [5].
  • This motif is conserved in eukaryotic PMS2 homologs and in MutL proteins from a number of bacterial species but is lacking in MutL proteins from bacteria that rely on d(GATC) methylation for strand discrimination in mismatch repair [5].
  • In addition, germ-line mutations in the mismatch-repair genes hMLH1 or hPMS2 were found in two families [6].
  • We observed microsatellite instability in the male germline, in tail, and in tumor DNA of PMS2-deficient animals [7].
  • PMS2-deficient animals appear prone to sarcomas and lymphomas [7].
 

Chemical compound and disease context of PMS2

 

Biological context of PMS2

 

Anatomical context of PMS2

  • With IHC, adding PMS2 staining led to the identification of an additional 23% of subjects with an hMLH1 germ-line mutation (35 carriers were tested) [13].
  • Truncation of the mismatch repair protein PMS2 during the neoplastic transformation of human breast epithelial cells in vitro [14].
  • Co-expression in doubly mutant Mlh1(-/-); Pms2(-/-) fibroblasts showed that MLH1-L749X was unable to stabilize PMS2 [15].
  • In contrast, there was tandem loss of MLH1 and PMS2 in zones of LGD (1/1) or HGD (3/5) and early carcinoma (2/4; with concordant loss in associated HGD) but retention in SSA areas (11/11) and normal mucosa (11/11) [16].
  • A deficient expression of MLH1 and PMS2 without hMLH1 inactivation was observed only in one giant cell GBM [17].
 

Associations of PMS2 with chemical compounds

  • We found the CTH to be essential for suppression of spontaneous mutation, activation of a cytotoxic response to 6-thioguanine, and maintenance of normal steady state levels of PMS2 [15].
  • Moreover, stimulation of the p73 proapoptotic function by cisplatin requires PMS2 [18].
  • The previously published PMS2 cDNA sequence lacks an upstream in-frame stop codon preceding the presumptive initiating methionine [19].
  • To study the significance of these motifs to mismatch repair, we have expressed in insect cells wild type human MutLalpha and forms altered in conserved glutamic acid residues, predicted to catalyze ATP hydrolysis of Mlh1, Pms2, or both [20].
  • We report here the X-ray crystal structures of the conserved N-terminal 40 kDa fragment of hPMS2, NhPMS2, and its complexes with ATPgammaS and ADP at 1.95, 2.7 and 2.7 A resolution, respectively [21].
 

Physical interactions of PMS2

  • Although the hMLH1 protein has been found to copurify with another MMR protein hPMS2 as a heterodimer, their function in MMR is unknown [22].
 

Regulatory relationships of PMS2

  • Truncation of the C-terminus of human MLH1 blocks intracellular stabilization of PMS2 and disrupts DNA mismatch repair [15].
  • Transgenic expression of hMGMT significantly but incompletely blocked MNU lymphomagenesis in PMS2-/- mice [4].
  • Western blot analysis and immunohistochemistry demonstrated that hMLH1 and hPMS2 are widely expressed nuclear proteins with a distribution pattern very similar to that previously described for hMSH2 [23].
 

Other interactions of PMS2

  • In order to better understand the consequences of MMR deficiency in mammalian organisms, mice deficient for the Pms2, Mlh1 and Msh2 MMR gene homologues have been generated [24].
  • Mutagenesis of yeast MW104-1B strain has identified the uncharacterized PMS6 DNA mismatch repair gene locus and additional alleles of existing PMS1, PMS2 and MSH2 genes [25].
  • Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation [26].
  • Our data confirm that, regardless of the type of families and the tumor phenotype, hPMS1, hPMS2, and hMSH6 germline mutations are rare in familial aggregation of colorectal cancers [27].
  • These data suggest that PMS(-/-) mice are hypersensitive to MNU, that there are different pathways responsible for spontaneous and MNU induced thymic lymphomas in PMS2(-/-) mice, and that overexpression of hMGMT protects the mice by blocking non-K-ras pathways [8].
 

Analytical, diagnostic and therapeutic context of PMS2

  • As candidates for PMS2 mutations, we selected seven patients whose colon tumors stained negative for PMS2 and positive for MLH1 by immunohistochemistry [26].
  • In an attempt to gain novel insights into the function of MMR proteins in human cells, we searched for interacting partners of the MutL homologues MLH1 and PMS2 by tandem affinity purification and of PMS1 by large scale immunoprecipitation [28].
  • To evaluate the 5' terminus of the PMS2 coding region further, we isolated additional cDNA clones, RT-PCR products, and the corresponding 5' genomic segment of the PMS2 locus [19].
  • In the present study in order to determine the role of those mutations in the hPMS2 protein activity, we used western blotting, protein truncation test and MMR activity assay employing HBEC cells [14].
  • Using gene targeting in embryonic stem cells, we have derived mice with a null mutation in a DNA mismatch repair gene homolog, PMS2 [7].

References

  1. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Truninger, K., Menigatti, M., Luz, J., Russell, A., Haider, R., Gebbers, J.O., Bannwart, F., Yurtsever, H., Neuweiler, J., Riehle, H.M., Cattaruzza, M.S., Heinimann, K., Schär, P., Jiricny, J., Marra, G. Gastroenterology (2005) [Pubmed]
  2. Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Hendriks, Y.M., Jagmohan-Changur, S., van der Klift, H.M., Morreau, H., van Puijenbroek, M., Tops, C., van Os, T., Wagner, A., Ausems, M.G., Gomez, E., Breuning, M.H., Bröcker-Vriends, A.H., Vasen, H.F., Wijnen, J.T. Gastroenterology (2006) [Pubmed]
  3. Common variants in mismatch repair genes and risk of invasive ovarian cancer. Song, H., Ramus, S.J., Quaye, L., Dicioccio, R.A., Tyrer, J., Lomas, E., Shadforth, D., Hogdall, E., Hogdall, C., McGuire, V., Whittemore, A.S., Easton, D.F., Ponder, B.A., Kjaer, S.K., Pharoah, P.D., Gayther, S.A. Carcinogenesis (2006) [Pubmed]
  4. Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT. Qin, X., Liu, L., Gerson, S.L. Oncogene (1999) [Pubmed]
  5. Endonucleolytic function of MutLalpha in human mismatch repair. Kadyrov, F.A., Dzantiev, L., Constantin, N., Modrich, P. Cell (2006) [Pubmed]
  6. The molecular basis of Turcot's syndrome. Hamilton, S.R., Liu, B., Parsons, R.E., Papadopoulos, N., Jen, J., Powell, S.M., Krush, A.J., Berk, T., Cohen, Z., Tetu, B. N. Engl. J. Med. (1995) [Pubmed]
  7. Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis. Baker, S.M., Bronner, C.E., Zhang, L., Plug, A.W., Robatzek, M., Warren, G., Elliott, E.A., Yu, J., Ashley, T., Arnheim, N., Flavell, R.A., Liskay, R.M. Cell (1995) [Pubmed]
  8. Transgenic expression of human MGMT blocks the hypersensitivity of PMS2-deficient mice to low dose MNU thymic lymphomagenesis. Qin, X., Zhou, H., Liu, L., Gerson, S.L. Carcinogenesis (1999) [Pubmed]
  9. Aspirin suppresses the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection. Rüschoff, J., Wallinger, S., Dietmaier, W., Bocker, T., Brockhoff, G., Hofstädter, F., Fishel, R. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  10. hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents. Brown, R., Hirst, G.L., Gallagher, W.M., McIlwrath, A.J., Margison, G.P., van der Zee, A.G., Anthoney, D.A. Oncogene (1997) [Pubmed]
  11. Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells. Mihaylova, V.T., Bindra, R.S., Yuan, J., Campisi, D., Narayanan, L., Jensen, R., Giordano, F., Johnson, R.S., Rockwell, S., Glazer, P.M. Mol. Cell. Biol. (2003) [Pubmed]
  12. Mutator phenotype in human hematopoietic neoplasms and its association with deletions disabling DNA repair genes and bcl-2 rearrangements. Indraccolo, S., Minuzzo, S., Nicoletti, L., Cretella, E., Simon, M., Papakonstantinou, G., Hehlmann, R., Mion, M., Bertorelle, R., Roganovic, J., Chieco-Bianchi, L. Blood (1999) [Pubmed]
  13. Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer. de Jong, A.E., van Puijenbroek, M., Hendriks, Y., Tops, C., Wijnen, J., Ausems, M.G., Meijers-Heijboer, H., Wagner, A., van Os, T.A., Bröcker-Vriends, A.H., Vasen, H.F., Morreau, H. Clin. Cancer Res. (2004) [Pubmed]
  14. Truncation of the mismatch repair protein PMS2 during the neoplastic transformation of human breast epithelial cells in vitro. Balogh, G.A., Russo, I.H., Russo, J. Int. J. Oncol. (2004) [Pubmed]
  15. Truncation of the C-terminus of human MLH1 blocks intracellular stabilization of PMS2 and disrupts DNA mismatch repair. Mohd, A.B., Palama, B., Nelson, S.E., Tomer, G., Nguyen, M., Huo, X., Buermeyer, A.B. DNA Repair (Amst.) (2006) [Pubmed]
  16. Sessile serrated adenomas with low- and high-grade dysplasia and early carcinomas: an immunohistochemical study of serrated lesions "caught in the act". Sheridan, T.B., Fenton, H., Lewin, M.R., Burkart, A.L., Iacobuzio-Donahue, C.A., Frankel, W.L., Montgomery, E. Am. J. Clin. Pathol. (2006) [Pubmed]
  17. Molecular mechanisms associated with chromosomal and microsatellite instability in sporadic glioblastoma multiforme. Martinez, R., Schackert, H.K., Plaschke, J., Baretton, G., Appelt, H., Schackert, G. Oncology (2004) [Pubmed]
  18. Interaction of mismatch repair protein PMS2 and the p53-related transcription factor p73 in apoptosis response to cisplatin. Shimodaira, H., Yoshioka-Yamashita, A., Kolodner, R.D., Wang, J.Y. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  19. Analysis of the 5' region of PMS2 reveals heterogeneous transcripts and a novel overlapping gene. Nicolaides, N.C., Kinzler, K.W., Vogelstein, B. Genomics (1995) [Pubmed]
  20. Contribution of human mlh1 and pms2 ATPase activities to DNA mismatch repair. Tomer, G., Buermeyer, A.B., Nguyen, M.M., Liskay, R.M. J. Biol. Chem. (2002) [Pubmed]
  21. Structure and function of the N-terminal 40 kDa fragment of human PMS2: a monomeric GHL ATPase. Guarné, A., Junop, M.S., Yang, W. EMBO J. (2001) [Pubmed]
  22. The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer. Guerrette, S., Acharya, S., Fishel, R. J. Biol. Chem. (1999) [Pubmed]
  23. Expression of the DNA mismatch repair proteins hMLH1 and hPMS2 in normal human tissues. Fink, D., Nebel, S., Aebi, S., Zheng, H., Kim, H.K., Christen, R.D., Howell, S.B. Br. J. Cancer (1997) [Pubmed]
  24. DNA mismatch repair deficient mice in cancer research. Prolla, T.A., Abuin, A., Bradley, A. Semin. Cancer Biol. (1996) [Pubmed]
  25. Mutagenesis of yeast MW104-1B strain has identified the uncharacterized PMS6 DNA mismatch repair gene locus and additional alleles of existing PMS1, PMS2 and MSH2 genes. Jeyaprakash, A., Welch, J.W., Fogel, S. Mutat. Res. (1994) [Pubmed]
  26. Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation. Nakagawa, H., Lockman, J.C., Frankel, W.L., Hampel, H., Steenblock, K., Burgart, L.J., Thibodeau, S.N., de la Chapelle, A. Cancer Res. (2004) [Pubmed]
  27. Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer. Wang, Q., Lasset, C., Desseigne, F., Saurin, J.C., Maugard, C., Navarro, C., Ruano, E., Descos, L., Trillet-Lenoir, V., Bosset, J.F., Puisieux, A. Hum. Genet. (1999) [Pubmed]
  28. Characterization of the Interactome of the Human MutL Homologues MLH1, PMS1, and PMS2. Cannavo, E., Gerrits, B., Marra, G., Schlapbach, R., Jiricny, J. J. Biol. Chem. (2007) [Pubmed]
 
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