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MLH3  -  mutL homolog 3

Homo sapiens

Synonyms: DNA mismatch repair protein Mlh3, MutL protein homolog 3
 
 
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Disease relevance of MLH3

 

High impact information on MLH3

  • We identified ten different germline MLH3 variants, one frameshift and nine missense mutations, in 12 patients suspected of HNPCC [3].
  • Cells in culture stably expressing a dominant-negative MLH3 protein exhibit microsatellite instability [6].
  • MLH3 is more similar to mismatch repair proteins from yeast, plants, worms and bacteria than to any known mammalian protein, suggesting that its conserved sequence may confer unique functions in mice and humans [6].
  • 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].
  • The DNA mismatch-repair MLH3 protein interacts with MSH4 in meiotic cells, supporting a role for this MutL homolog in mammalian meiotic recombination [8].
 

Biological context of MLH3

  • To further evaluate the role of MLH3 in CRC predisposition, we analyzed 30 Finnish CRC cases for germline mutations by sequencing [1].
  • 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 [9].
  • Furthermore, MLH3 nonsense mutations were identified in two of 12 microsatellite stable (MSS) tumors with 14q24 loss of heterozygosity [10].
  • There was no evidence of MLH3 promoter methylation based on combined bisulfite restriction analysis [4].
  • The results of the various methods are self-consistent and the equilibrium model includes the species MLH4, MLH3, MLH2, MLH, ML, MLH(-1), MLH(-2) and several hydrolysis products (where H4L denotes oxidized glutathione); individual formation constants and spectra are given [11].
 

Anatomical context of MLH3

 

Other interactions of MLH3

  • We now show that the hMLH1/hMLH3 heterodimer, hMutLgamma, can also assist in the repair of base-base mismatches and single extrahelical nucleotides in vitro [2].
  • We further demonstrate that the meiosis-specific MSH4 protein, known to participate to meiotic recombination, is co-immunoprecipitated with MLH3 from mouse meiotic cell extracts [8].
  • Similar to MSH3 and MSH6, MLH3 harbors mononucleotide repeats, ie, (A(6))-(A(9)), in its coding region, which makes it a putative target for somatic mutations in MSI-positive tumors [12].
  • Two additional MMR genes, MLH3 and PMS1, have also been proposed to play a role in Lynch syndrome predisposition, but the clinical significance of mutations in these genes is less clear [13].
  • Interestingly, these residues in hPMS2 and hMLH3 may form coiled-coil structures as predicted by the MULTICOIL program [14].
 

Analytical, diagnostic and therapeutic context of MLH3

References

  1. Little evidence for involvement of MLH3 in colorectal cancer predisposition. Hienonen, T., Laiho, P., Salovaara, R., Mecklin, J.P., Järvinen, H., Sistonen, P., Peltomäki, P., Lehtonen, R., Nupponen, N.N., Launonen, V., Karhu, A., Aaltonen, L.A. Int. J. Cancer (2003) [Pubmed]
  2. Expression of the MutL homologue hMLH3 in human cells and its role in DNA mismatch repair. Cannavo, E., Marra, G., Sabates-Bellver, J., Menigatti, M., Lipkin, S.M., Fischer, F., Cejka, P., Jiricny, J. Cancer Res. (2005) [Pubmed]
  3. A role for MLH3 in hereditary nonpolyposis colorectal cancer. Wu, Y., Berends, M.J., Sijmons, R.H., Mensink, R.G., Verlind, E., Kooi, K.A., van der Sluis, T., Kempinga, C., van dDer Zee, A.G., Hollema, H., Buys, C.H., Kleibeuker, J.H., Hofstra, R.M. Nat. Genet. (2001) [Pubmed]
  4. MLH3 mutation in endometrial cancer. Taylor, N.P., Powell, M.A., Gibb, R.K., Rader, J.S., Huettner, P.C., Thibodeau, S.N., Mutch, D.G., Goodfellow, P.J. Cancer Res. (2006) [Pubmed]
  5. Mutation screening of mismatch repair gene Mlh3 in familial esophageal cancer. Liu, H.X., Li, Y., Jiang, X.D., Yin, H.N., Zhang, L., Wang, Y., Yang, J. World J. Gastroenterol. (2006) [Pubmed]
  6. MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability. Lipkin, S.M., Wang, V., Jacoby, R., Banerjee-Basu, S., Baxevanis, A.D., Lynch, H.T., Elliott, R.M., Collins, F.S. Nat. Genet. (2000) [Pubmed]
  7. Mediating mismatch repair. Jiricny, J. Nat. Genet. (2000) [Pubmed]
  8. The DNA mismatch-repair MLH3 protein interacts with MSH4 in meiotic cells, supporting a role for this MutL homolog in mammalian meiotic recombination. Santucci-Darmanin, S., Neyton, S., Lespinasse, F., Saunières, A., Gaudray, P., Paquis-Flucklinger, V. Hum. Mol. Genet. (2002) [Pubmed]
  9. 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]
  10. Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers. Lipkin, S.M., Wang, V., Stoler, D.L., Anderson, G.R., Kirsch, I., Hadley, D., Lynch, H.T., Collins, F.S. Hum. Mutat. (2001) [Pubmed]
  11. The system VO2+ +oxidized glutathione: a potentiometric and spectroscopic study. Pessoa, J.C., Tomaz, I., Kiss, T., Buglyó, P. J. Inorg. Biochem. (2001) [Pubmed]
  12. Germline and somatic mutation analysis of MLH3 in MSI-positive colorectal cancer. Loukola, A., Vilkki, S., Singh, J., Launonen, V., Aaltonen, L.A. Am. J. Pathol. (2000) [Pubmed]
  13. Lynch syndrome genes. Peltomäki, P. Fam. Cancer (2005) [Pubmed]
  14. The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2. Kondo, E., Horii, A., Fukushige, S. Nucleic Acids Res. (2001) [Pubmed]
  15. The role of hMLH3 in familial colorectal cancer. Liu, H.X., Zhou, X.L., Liu, T., Werelius, B., Lindmark, G., Dahl, N., Lindblom, A. Cancer Res. (2003) [Pubmed]
  16. Conditional nuclear localization of hMLH3 suggests a minor activity in mismatch repair and supports its role as a low-risk gene in HNPCC. Korhonen, M.K., Raevaara, T.E., Lohi, H., Nystr??m, M. Oncol. Rep. (2007) [Pubmed]
 
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