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MLH1  -  mutL homolog 1

Homo sapiens

Synonyms: COCA2, DNA mismatch repair protein Mlh1, FCC2, HNPCC, HNPCC2, ...
 
 
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Disease relevance of MLH1

 

Psychiatry related information on MLH1

 

High impact information on MLH1

  • Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1 . We propose a robust new marker panel to classify CIMP+ tumors [6].
  • Association studies identified a new MLH1 variant (415G-->C, resulting in the amino acid substitution D132H) in approximately 1.3% of Israeli individuals with CRC self-described as Jewish, Christian and Muslim. MLH1 415C confers clinically significant susceptibility to CRC [1].
  • The DNA repair picture in humans becomes more complete with the identification of MLH3, a homologue of MutL and a heterodimeric partner of MLH1 [7].
  • Epigenetic events can also facilitate genetic damage, as illustrated by the increased mutagenicity of 5-methylcytosine and the silencing of the MLH1 mismatch repair gene by DNA methylation in colorectal tumours [8].
  • RESULTS: Mutations of MSH2 or MLH1 were found in 47 of the 184 kindreds (26 percent) [2].
 

Chemical compound and disease context of MLH1

 

Biological context of MLH1

  • Most such cancers have the CpG island methylator phenotype (CIMP+) with methylation and transcriptional silencing of the mismatch repair gene MLH1 [14].
  • Germline epimutations should be suspected in younger individuals without a family history who present with a microsatellite unstable tumor showing loss of MLH1 expression [15].
  • CONCLUSIONS: Germline MLH1 epimutations are functionally equivalent to an inactivating mutation and produce a clinical phenotype that resembles HNPCC [15].
  • MLH1 and MLH3 have been shown to mark late-meiotic nodules that correlate well with--and are thought to give rise to--the sites of reciprocal recombination between homologous chromosomes, which suggests a possible 10-fold variation in the processing of nascent recombination events [16].
  • In the MSI-high group, one MSH6 missense mutation was found, but the same patient also had an MLH1 mutation, which may explain the MSI-high phenotype [17].
 

Anatomical context of MLH1

 

Associations of MLH1 with chemical compounds

  • METHODS: A cohort of 160 probands from HNPCC families who did not harbor germline sequence mutations in the mismatch repair genes were screened for methylation of the MLH1 and EPM2AIP1 promoters by combined bisulfite and restriction analyses [15].
  • In addition, treatment of cells with the iron chelator desferrioxamine also reduced MLH1 and PMS2 levels, in keeping with low oxygen tension being the stress signal that provokes the altered MMR gene expression [20].
  • A role for the Mut L homologue-1 (MLH1) protein, a necessary component of DNA mismatch repair (MMR), in G2-M cell cycle checkpoint arrest after 6-thioguanine (6-TG) exposure was suggested previously [18].
  • Introduction of a nocodazole-induced G2-M block, which corrected the MLH1-mediated G2-M arrest deficiency in HCT116 cells, clearly demonstrated that HCT116 and HCT116 3-6 cells did not differ in G1 arrest or G1-S cell cycle transition after IR [18].
  • We have previously demonstrated that both the MLH1 and MSH2 status impact the DNA levels of the halogenated thymidine (dThd) analogues iododeoxyuridine (IdUrd) and bromodeoxyuridine (BrdUrd), and thereby radiosensitization induced by these analogues, indirectly implicating both mismatch repair (MMR) proteins in the removal of these bases from DNA [21].
 

Physical interactions of MLH1

  • Here we show that hMSH4 interacts with hMLH1 [22].
  • In addition, hExoI forms an immunoprecipitable complex with hMLH1/hPMS2 in vivo [23].
  • Although the hMLH1 protein has been found to copurify with another MMR protein hPMS2 as a heterodimer, their function in MMR is unknown [24].
  • None of the complex atypical hyperplasias in group 1 had high-level microsatellite instability or loss of hMLH1/hMSH2 protein expression [25].
  • In this study, we have identified the BRCA1 binding domains to MLH1 and demonstrated that three distinct mutations in one of these interaction domains can produce, in vitro, a microsatellite instability phenotype, one of the hallmarks of an imbalance in the mismatch DNA repair machinery [26].
 

Enzymatic interactions of MLH1

  • Sixty five percent of the patients deleted at hMLH1 were also deleted at hMSH3 [27].
 

Co-localisations of MLH1

  • During this transition, MLH1 foci begin to appear and colocalize with MSH4 [22].
 

Regulatory relationships of MLH1

  • MSH2 was expressed in all stages of spermatogenesis up to but excluding mature sperm whereas MLH1 was predominantly expressed in premeiotic germ cells [28].
  • Truncation of the C-terminus of human MLH1 blocks intracellular stabilization of PMS2 and disrupts DNA mismatch repair [29].
  • We now show that hPMS1 is expressed in human cells and that it interacts with hMLH1 with high affinity to form the heterodimer hMutLbeta [30].
  • HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence assembly of hMutLalpha and hMLH1-hEXO1 complexes [31].
  • HOXA5 regulates hMLH1 expression in breast cancer cells [32].
 

Other interactions of MLH1

 

Analytical, diagnostic and therapeutic context of MLH1

References

  1. The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer. Lipkin, S.M., Rozek, L.S., Rennert, G., Yang, W., Chen, P.C., Hacia, J., Hunt, N., Shin, B., Fodor, S., Kokoris, M., Greenson, J.K., Fearon, E., Lynch, H., Collins, F., Gruber, S.B. Nat. Genet. (2004) [Pubmed]
  2. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. Wijnen, J.T., Vasen, H.F., Khan, P.M., Zwinderman, A.H., van der Klift, H., Mulder, A., Tops, C., Møller, P., Fodde, R. N. Engl. J. Med. (1998) [Pubmed]
  3. Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation. Gallinger, S., Aronson, M., Shayan, K., Ratcliffe, E.M., Gerstle, J.T., Parkin, P.C., Rothenmund, H., Croitoru, M., Baumann, E., Durie, P.R., Weksberg, R., Pollett, A., Riddell, R.H., Ngan, B.Y., Cutz, E., Lagarde, A.E., Chan, H.S. Gastroenterology (2004) [Pubmed]
  4. Analysis of hMLH1 missense mutations in East Asian patients with suspected hereditary nonpolyposis colorectal cancer. Fan, Y., Wang, W., Zhu, M., Zhou, J., Peng, J., Xu, L., Hua, Z., Gao, X., Wang, Y. Clin. Cancer Res. (2007) [Pubmed]
  5. Effects of dietary intake and genetic factors on hypermethylation of the hMLH1 gene promoter in gastric cancer. Nan, H.M., Song, Y.J., Yun, H.Y., Park, J.S., Kim, H. World J. Gastroenterol. (2005) [Pubmed]
  6. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Weisenberger, D.J., Siegmund, K.D., Campan, M., Young, J., Long, T.I., Faasse, M.A., Kang, G.H., Widschwendter, M., Weener, D., Buchanan, D., Koh, H., Simms, L., Barker, M., Leggett, B., Levine, J., Kim, M., French, A.J., Thibodeau, S.N., Jass, J., Haile, R., Laird, P.W. Nat. Genet. (2006) [Pubmed]
  7. Mediating mismatch repair. Jiricny, J. Nat. Genet. (2000) [Pubmed]
  8. Cancer epigenetics comes of age. Jones, P.A., Laird, P.W. Nat. Genet. (1999) [Pubmed]
  9. Role of the hMLH1 DNA mismatch repair protein in fluoropyrimidine-mediated cell death and cell cycle responses. Meyers, M., Wagner, M.W., Hwang, H.S., Kinsella, T.J., Boothman, D.A. Cancer Res. (2001) [Pubmed]
  10. DNA mismatch repair-dependent response to fluoropyrimidine-generated damage. Meyers, M., Wagner, M.W., Mazurek, A., Schmutte, C., Fishel, R., Boothman, D.A. J. Biol. Chem. (2005) [Pubmed]
  11. Mismatch repair and treatment resistance in ovarian cancer. Helleman, J., van Staveren, I.L., Dinjens, W.N., van Kuijk, P.F., Ritstier, K., Ewing, P.C., van der Burg, M.E., Stoter, G., Berns, E.M. BMC Cancer (2006) [Pubmed]
  12. DNA mismatch repair genes in renal cell carcinoma. Deguchi, M., Shiina, H., Igawa, M., Kaneuchi, M., Nakajima, K., Dahiya, R. J. Urol. (2003) [Pubmed]
  13. MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Esteller, M., Levine, R., Baylin, S.B., Ellenson, L.H., Herman, J.G. Oncogene (1998) [Pubmed]
  14. P14 methylation in human colon cancer is associated with microsatellite instability and wild-type p53. Shen, L., Kondo, Y., Hamilton, S.R., Rashid, A., Issa, J.P. Gastroenterology (2003) [Pubmed]
  15. MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. Hitchins, M., Williams, R., Cheong, K., Halani, N., Lin, V.A., Packham, D., Ku, S., Buckle, A., Hawkins, N., Burn, J., Gallinger, S., Goldblatt, J., Kirk, J., Tomlinson, I., Scott, R., Spigelman, A., Suter, C., Martin, D., Suthers, G., Ward, R. Gastroenterology (2005) [Pubmed]
  16. Extreme heterogeneity in the molecular events leading to the establishment of chiasmata during meiosis i in human oocytes. Lenzi, M.L., Smith, J., Snowden, T., Kim, M., Fishel, R., Poulos, B.K., Cohen, P.E. Am. J. Hum. Genet. (2005) [Pubmed]
  17. Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Wu, Y., Berends, M.J., Mensink, R.G., Kempinga, C., Sijmons, R.H., van Der Zee, A.G., Hollema, H., Kleibeuker, J.H., Buys, C.H., Hofstra, R.M. Am. J. Hum. Genet. (1999) [Pubmed]
  18. Defective expression of the DNA mismatch repair protein, MLH1, alters G2-M cell cycle checkpoint arrest following ionizing radiation. Davis, T.W., Wilson-Van Patten, C., Meyers, M., Kunugi, K.A., Cuthill, S., Reznikoff, C., Garces, C., Boland, C.R., Kinsella, T.J., Fishel, R., Boothman, D.A. Cancer Res. (1998) [Pubmed]
  19. Reliable and sensitive detection of premature termination mutations using a protein truncation test designed to overcome problems of nonsense-mediated mRNA instability. Bateman, J.F., Freddi, S., Lamandé, S.R., Byers, P., Nasioulas, S., Douglas, J., Otway, R., Kohonen-Corish, M., Edkins, E., Forrest, S. Hum. Mutat. (1999) [Pubmed]
  20. 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]
  21. Role of MutSalpha in the recognition of iododeoxyuridine in DNA. Berry, S.E., Loh, T., Yan, T., Kinsella, T.J. Cancer Res. (2003) [Pubmed]
  22. MSH4 acts in conjunction with MLH1 during mammalian meiosis. Santucci-Darmanin, S., Walpita, D., Lespinasse, F., Desnuelle, C., Ashley, T., Paquis-Flucklinger, V. FASEB J. (2000) [Pubmed]
  23. The interaction of DNA mismatch repair proteins with human exonuclease I. Schmutte, C., Sadoff, M.M., Shim, K.S., Acharya, S., Fishel, R. J. Biol. Chem. (2001) [Pubmed]
  24. The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer. Guerrette, S., Acharya, S., Fishel, R. J. Biol. Chem. (1999) [Pubmed]
  25. Molecular analysis of endometrial hyperplasia in HNPCC-suspicious patients may predict progression to endometrial carcinoma. Sutter, C., Dallenbach-Hellweg, G., Schmidt, D., Baehring, J., Bielau, S., von Knebel Doeberitz, M., Gebert, J. Int. J. Gynecol. Pathol. (2004) [Pubmed]
  26. In vitro analysis of genomic instability triggered by BRCA1 missense mutations. Quaresima, B., Faniello, M.C., Baudi, F., Crugliano, T., Cuda, G., Costanzo, F., Venuta, S. Hum. Mutat. (2006) [Pubmed]
  27. High resolution deletion mapping reveals frequent allelic losses at the DNA mismatch repair loci hMLH1 and hMSH3 in non-small cell lung cancer. Benachenhou, N., Guiral, S., Gorska-Flipot, I., Labuda, D., Sinnett, D. Int. J. Cancer (1998) [Pubmed]
  28. Mismatch repair gene expression and genetic instability in testicular germ cell tumor. Velasco, A., Riquelme, E., Schultz, M., Wistuba, I.I., Villarroel, L., Pizarro, J., Berlin, A., Ittmann, M., Koh, M.S., Leach, F.S. Cancer Biol. Ther. (2004) [Pubmed]
  29. 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]
  30. Identification of hMutLbeta, a heterodimer of hMLH1 and hPMS1. Räschle, M., Marra, G., Nyström-Lahti, M., Schär, P., Jiricny, J. J. Biol. Chem. (1999) [Pubmed]
  31. HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence assembly of hMutLalpha and hMLH1-hEXO1 complexes. Jäger, A.C., Rasmussen, M., Bisgaard, H.C., Singh, K.K., Nielsen, F.C., Rasmussen, L.J. Oncogene (2001) [Pubmed]
  32. HOXA5 regulates hMLH1 expression in breast cancer cells. Duriseti, S., Winnard, P.T., Mironchik, Y., Vesuna, F., Raman, A., Raman, V. Neoplasia (2006) [Pubmed]
  33. Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DNA mismatch repair. Prolla, T.A., Baker, S.M., Harris, A.C., Tsao, J.L., Yao, X., Bronner, C.E., Zheng, B., Gordon, M., Reneker, J., Arnheim, N., Shibata, D., Bradley, A., Liskay, R.M. Nat. Genet. (1998) [Pubmed]
  34. Epigenetic and genetic alterations in duodenal carcinomas are distinct from biliary and ampullary carcinomas. Kim, S.G., Chan, A.O., Wu, T.T., Issa, J.P., Hamilton, S.R., Rashid, A. Gastroenterology (2003) [Pubmed]
  35. MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1. Bellacosa, A., Cicchillitti, L., Schepis, F., Riccio, A., Yeung, A.T., Matsumoto, Y., Golemis, E.A., Genuardi, M., Neri, G. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  36. ATM-mediated stabilization of hMutL DNA mismatch repair proteins augments p53 activation during DNA damage. Luo, Y., Lin, F.T., Lin, W.C. Mol. Cell. Biol. (2004) [Pubmed]
  37. Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients. Ibanez de Caceres, I., Battagli, C., Esteller, M., Herman, J.G., Dulaimi, E., Edelson, M.I., Bergman, C., Ehya, H., Eisenberg, B.L., Cairns, P. Cancer Res. (2004) [Pubmed]
  38. 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]
  39. Reduced MLH1 expression after chemotherapy is an indicator for poor prognosis in esophageal cancers. Kishi, K., Doki, Y., Yano, M., Yasuda, T., Fujiwara, Y., Takiguchi, S., Kim, S., Higuchi, I., Monden, M. Clin. Cancer Res. (2003) [Pubmed]
  40. A homozygous mutation in MSH6 causes Turcot syndrome. Hegde, M.R., Chong, B., Blazo, M.E., Chin, L.H., Ward, P.A., Chintagumpala, M.M., Kim, J.Y., Plon, S.E., Richards, C.S. Clin. Cancer Res. (2005) [Pubmed]
  41. Myc down-regulation sensitizes melanoma cells to radiotherapy by inhibiting MLH1 and MSH2 mismatch repair proteins. Bucci, B., D'Agnano, I., Amendola, D., Citti, A., Raza, G.H., Miceli, R., De Paula, U., Marchese, R., Albini, S., Felsani, A., Brunetti, E., Vecchione, A. Clin. Cancer Res. (2005) [Pubmed]
  42. Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in northern Sweden. Cederquist, K., Emanuelsson, M., Göransson, I., Holinski-Feder, E., Müller-Koch, Y., Golovleva, I., Grönberg, H. Int. J. Cancer (2004) [Pubmed]
 
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