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Gene Review

Mlh1  -  mutL homolog 1 (E. coli)

Mus musculus

Synonyms: 1110035C23Rik, AI317206, AI325952, AI561766, DNA mismatch repair protein Mlh1, ...
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Disease relevance of Mlh1

  • The findings may provide a basis for understanding the greater predisposition to intestinal cancer of Mlh1(-/-) mice [1].
  • We showed that mice heterozygous and homozygous for the Mlh1 gene are predisposed to developing tumors of the gastrointestinal (GI) tract, lymphomas, and a number of other tumor types [2].
  • We find that these doubly mutant mice develop more than three times the number of intestinal adenomas compared to Min/+ Mlh1+/+ or +/- mice but that these tumors do not show advanced progression in terms of tumor size or histological appearance [3].
  • We have previously reported that the multiplicity of intestinal tumors is increased dramatically by crossing Apc1638N with an Mlh1-deficient mouse strain that represents an animal model of hereditary non-polyposis colorectal cancer (HNPCC) [4].
  • Mlh1 deficiency in Min/+ mice also led to an increase in cystic intestinal crypt multiplicity as well as enhancing desmoid tumorigenesis and epidermoid cyst development [3].

High impact information on Mlh1

  • Mlh1-deficient spermatocytes exhibit high levels of prematurely separated chromosomes and arrest in first division meiosis [5].
  • Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over [5].
  • Here mice deficient in another mismatch repair gene, Mlh1, possess not only microsatellite instability but are also infertile (both males and females) [5].
  • Our results report direct molecular evidence for distinct CR and NCR pathways of DNA double-strand break (DSB) repair in mouse meiosis based on three observations: both CRs and NCRs require Spo11, NCR products have shorter conversion tracts than CRs, and only CRs require the MutL homolog Mlh1 [6].
  • We show that both products are formed from middle to late pachytene of meiotic prophase and provide evidence for an Mlh1-independent CR pathway, where mismatch repair does not require Mlh1 [6].

Chemical compound and disease context of Mlh1

  • The hypoxia-induced reduction in Mlh1 mRNA was prevented by the histone deacetylase inhibitor trichostatin A, suggesting that hypoxia causes decreased Mlh1 transcription via histone deacetylation [7].

Biological context of Mlh1

  • The higher mutation frequency in Mlh1(-/-) mice may be a consequence of some residual DNA repair capacity in the Pms2(-/-) animals [1].
  • Mice with mutations in Mlh1, Pms2 and Msh5 have defects in meiosis suggesting unique roles for these genes in gametogenesis [8].
  • We have also analyzed mice mutant for the mismatch repair genes Msh2, Mlh1, and Pms2, describing circumstances in which all of these strains show defective apoptosis, increased clonogenic survival, and increased mutation rate [9].
  • This haploinsufficient character of Mlh1 mutation was also observed in cell survival assays; Mgmt(-/-)Mlh1(+/-) cells were as resistant to MNU as were Mgmt(-/-)Mlh1(-/-) cells [10].
  • We also show that Mlh1 appears to localize to sites of crossing over on meiotic chromosomes [5].

Anatomical context of Mlh1

  • The frequency of switching is reduced, similarly to that of B cells singly deficient in Msh2 or Mlh1 [11].
  • Here, we extend these studies to the MutL homologues (MLH) Mlh1 and Pms2 by analysing the apoptotic response within the small intestine of gene targeted strains [12].
  • We have studied the formation of the first meiotic spindle in murine oocytes from mice homozygous for a targeted disruption of the DNA mismatch repair gene, Mlh1 [13].
  • The absence of Msh2 or Mlh1, two key molecules that mediate mismatch repair in eukaryotic cells, increases the frequency of mutation and also alters the response of some cells to apoptosis and cell cycle arrest [14].
  • Upon further analysis, the levels of halogenated dThd analogues in DNA were significantly lower (two to three times lower) in HCT116/3-6 cells than in HCT116 cells, and similar results were found in Mlh1+/+ spontaneously immortalized murine embryonic fibroblasts and fibroblasts from Mlh1 knockout mice [15].

Associations of Mlh1 with chemical compounds

  • Mgmt(-/-) cells are hypersensitive to the killing effect of N-methyl-N-nitrosourea (MNU) and this effect of MNU was overcome by introducing an additional mutation in the Mlh1 gene [10].
  • We show that treatment with temozolomide or 10mg/kg NMNU significantly increases mutation in both the Mlh1 and Pms2 mutant mice [12].
  • We next analysed the apoptotic response to 5-FU and temozolomide in doubly mutant Mbd4(-/-), Mlh1(-/-) mice but observed no additive decrease [16].
  • Similarly, we observed a cisplatin-induced G2 arrest in immortalized MMR deficient (Mlh1(-/-) and Pms2(-/-)) and WT MEFs. p53 deficient primary MEFs (p53(-/-)) exhibited both a clear G2 arrest and an increase in cells with a DNA content of 8N in response to cisplatin [17].
  • Our study was designed to determine whether troglitazone (TGZ) induces colonic tumor formation in normal C57BL/6J mice and enhances colorectal carcinogenesis in double mutant Apc1638N/+ Mlh1+/- mice fed a standard AIN-76A diet [18].

Regulatory relationships of Mlh1

  • In contrast to colon cancers from HNPCC patients, however, carcinomas of Mlh1-/- mice expressed p53 and showed a lack of transforming growth factor (TGF)-betaRII mutation, which resulted in the expression of TGF-betaRII protein [19].

Other interactions of Mlh1

  • Mlh1 can function in antibody class switch recombination independently of Msh2 [11].
  • Mutations of three of the four MutL homologues (Mlh1, Mlh3, and Pms2) result in meiotic defects [20].
  • IgG2b is the most affected, reduced by 75% in Mlh1-deficient animals [21].
  • The increased lymphomagenesis in Dnmt1 hypomorphic, Mlh1(-/-) mice may be due to a combination of several mechanisms, including elevated mutation rates, increased expression of proviral sequences or proto-oncogenes, and/or enhanced genomic instability [22].
  • This included prolonged association of gammaH2AX with sites of DNA damage, reduced sex body formation, diminished Rad51 foci and absence of Mlh1 foci in the pachytene stage [23].

Analytical, diagnostic and therapeutic context of Mlh1


  1. Different mutator phenotypes in Mlh1- versus Pms2-deficient mice. Yao, X., Buermeyer, A.B., Narayanan, L., Tran, D., Baker, S.M., Prolla, T.A., Glazer, P.M., Liskay, R.M., Arnheim, N. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  2. Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice. Edelmann, W., Yang, K., Kuraguchi, M., Heyer, J., Lia, M., Kneitz, B., Fan, K., Brown, A.M., Lipkin, M., Kucherlapati, R. Cancer Res. (1999) [Pubmed]
  3. Mlh1 deficiency enhances several phenotypes of Apc(Min)/+ mice. Shoemaker, A.R., Haigis, K.M., Baker, S.M., Dudley, S., Liskay, R.M., Dove, W.F. Oncogene (2000) [Pubmed]
  4. Tumor-associated Apc mutations in Mlh1-/- Apc1638N mice reveal a mutational signature of Mlh1 deficiency. Kuraguchi, M., Edelmann, W., Yang, K., Lipkin, M., Kucherlapati, R., Brown, A.M. Oncogene (2000) [Pubmed]
  5. Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. Baker, S.M., Plug, A.W., Prolla, T.A., Bronner, C.E., Harris, A.C., Yao, X., Christie, D.M., Monell, C., Arnheim, N., Bradley, A., Ashley, T., Liskay, R.M. Nat. Genet. (1996) [Pubmed]
  6. Crossover and noncrossover pathways in mouse meiosis. Guillon, H., Baudat, F., Grey, C., Liskay, R.M., de Massy, B. Mol. Cell (2005) [Pubmed]
  7. 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]
  8. Mouse models for colorectal cancer. Heyer, J., Yang, K., Lipkin, M., Edelmann, W., Kucherlapati, R. Oncogene (1999) [Pubmed]
  9. Analyzing tumor suppressor activities in the murine small intestine. Clarke, A.R., Sansom, O.J. Oncol. Res. (2003) [Pubmed]
  10. Roles of MGMT and MLH1 proteins in alkylation-induced apoptosis and mutagenesis. Takagi, Y., Takahashi, M., Sanada, M., Ito, R., Yamaizumi, M., Sekiguchi, M. DNA Repair (Amst.) (2003) [Pubmed]
  11. Mlh1 can function in antibody class switch recombination independently of Msh2. Schrader, C.E., Vardo, J., Stavnezer, J. J. Exp. Med. (2003) [Pubmed]
  12. Apoptosis and mutation in the murine small intestine: loss of Mlh1- and Pms2-dependent apoptosis leads to increased mutation in vivo. Sansom, O.J., Bishop, S.M., Court, H., Dudley, S., Liskay, R.M., Clarke, A.R. DNA Repair (Amst.) (2003) [Pubmed]
  13. Chromosomal influence on meiotic spindle assembly: abnormal meiosis I in female Mlh1 mutant mice. Woods, L.M., Hodges, C.A., Baart, E., Baker, S.M., Liskay, M., Hunt, P.A. J. Cell Biol. (1999) [Pubmed]
  14. The absence of Msh2 alters abelson virus pre-B-cell transformation by influencing p53 mutation. Jenab-Wolcott, J., Rodriguez-Correa, D., Reitmair, A.H., Mak, T., Rosenberg, N. Mol. Cell. Biol. (2000) [Pubmed]
  15. The mismatch repair protein, hMLH1, mediates 5-substituted halogenated thymidine analogue cytotoxicity, DNA incorporation, and radiosensitization in human colon cancer cells. Berry, S.E., Garces, C., Hwang, H.S., Kunugi, K., Meyers, M., Davis, T.W., Boothman, D.A., Kinsella, T.J. Cancer Res. (1999) [Pubmed]
  16. MBD4 deficiency reduces the apoptotic response to DNA-damaging agents in the murine small intestine. Sansom, O.J., Zabkiewicz, J., Bishop, S.M., Guy, J., Bird, A., Clarke, A.R. Oncogene (2003) [Pubmed]
  17. A role for mismatch repair in control of DNA ploidy following DNA damage. Strathdee, G., Sansom, O.J., Sim, A., Clarke, A.R., Brown, R. Oncogene (2001) [Pubmed]
  18. Peroxisome proliferator-activated receptor gamma agonist troglitazone induces colon tumors in normal C57BL/6J mice and enhances colonic carcinogenesis in Apc1638 N/+ Mlh1+/- double mutant mice. Yang, K., Fan, K.H., Lamprecht, S.A., Edelmann, W., Kopelovich, L., Kucherlapati, R., Lipkin, M. Int. J. Cancer (2005) [Pubmed]
  19. Accelerated growth of intestinal tumours after radiation exposure in Mlh1-knockout mice: evaluation of the late effect of radiation on a mouse model of HNPCC. Tokairin, Y., Kakinuma, S., Arai, M., Nishimura, M., Okamoto, M., Ito, E., Akashi, M., Miki, Y., Kawano, T., Iwai, T., Shimada, Y. International journal of experimental pathology. (2006) [Pubmed]
  20. Localization of MMR proteins on meiotic chromosomes in mice indicates distinct functions during prophase I. Kolas, N.K., Svetlanov, A., Lenzi, M.L., Macaluso, F.P., Lipkin, S.M., Liskay, R.M., Greally, J., Edelmann, W., Cohen, P.E. J. Cell Biol. (2005) [Pubmed]
  21. Reduced isotype switching in splenic B cells from mice deficient in mismatch repair enzymes. Schrader, C.E., Edelmann, W., Kucherlapati, R., Stavnezer, J. J. Exp. Med. (1999) [Pubmed]
  22. DNA methyltransferase deficiency modifies cancer susceptibility in mice lacking DNA mismatch repair. Trinh, B.N., Long, T.I., Nickel, A.E., Shibata, D., Laird, P.W. Mol. Cell. Biol. (2002) [Pubmed]
  23. Impaired meiotic DNA-damage repair and lack of crossing-over during spermatogenesis in BRCA1 full-length isoform deficient mice. Xu, X., Aprelikova, O., Moens, P., Deng, C.X., Furth, P.A. Development (2003) [Pubmed]
  24. Role for mismatch repair proteins Msh2, Mlh1, and Pms2 in immunoglobulin class switching shown by sequence analysis of recombination junctions. Schrader, C.E., Vardo, J., Stavnezer, J. J. Exp. Med. (2002) [Pubmed]
  25. Elevated mutant frequencies and increased C : G-->T : A transitions in Mlh1-/- versus Pms2-/- murine small intestinal epithelial cells. Baross-Francis, A., Makhani, N., Liskay, R.M., Jirik, F.R. Oncogene (2001) [Pubmed]
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