Biology:MLH3

Generic protein structure example

DNA mismatch repair protein Mlh3 is a protein that in humans is encoded by the MLH3 gene.

Function

This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. Orthologs of human MLH3 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae.

Meiosis

In addition to its role in DNA mismatch repair, MLH3 protein is also involved in meiotic crossing over. MLH3 forms a heterodimer with MLH1 that appears to be necessary for mouse oocytes to progress through metaphase II of meiosis.

A current model of meiotic recombination, initiated by a double-strand break or gap, followed by pairing with an homologous chromosome and strand invasion to initiate the recombinational repair process. Repair of the gap can lead to crossover (CO) or non-crossover (NCO) of the flanking regions. CO recombination is thought to occur by the Double Holliday Junction (DHJ) model, illustrated on the right, above. NCO recombinants are thought to occur primarily by the Synthesis Dependent Strand Annealing (SDSA) model, illustrated on the left, above. Most recombination events appear to be the SDSA type.

The MLH1-MLH3 heterodimers promote crossovers. Recombination during meiosis is often initiated by a DNA double-strand break (DSB) as illustrated in the accompanying diagram. During recombination, sections of DNA at the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" the DNA of a homologous chromosome that is not broken forming a displacement loop (D-loop). After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover (CO) or a non-crossover (NCO) recombinant (see Genetic recombination. The pathway leading to a CO involves a double Holliday junction (DHJ) intermediate. Holliday junctions need to be resolved for CO recombination to be completed.

In the budding yeast Saccharomyces cerevisiae, as in the mouse, MLH3 forms a heterodimer with MLH1. Meiotic CO requires resolution of Holliday junctions through actions of the MLH1-MLH3 heterodimer. The MLH1-MLH3 heterodimer is an endonuclease that makes single-strand breaks in supercoiled double-stranded DNA. MLH1-MLH3 binds specifically to Holliday junctions and may act as part of a larger complex to process Holliday junctions during meiosis. MLH1-MLH3 heterodimer (MutL gamma) together with Exo1 and Sgs1 (ortholog of Bloom syndrome helicase) define a joint molecule resolution pathway that produces the majority of crossovers in budding yeast and, by inference, in mammals.

Interactions

MLH3 has been shown to interact with MSH4.

Further reading

• "Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease". Nature 375 (6534): 754–60. Jun 1995. doi:10.1038/375754a0. PMID 7596406. Bibcode: 1995Natur.375..754S. 
• "The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2". Nucleic Acids Research 29 (8): 1695–702. Apr 2001. doi:10.1093/nar/29.8.1695. PMID 11292842. 
• "Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers". Human Mutation 17 (5): 389–96. May 2001. doi:10.1002/humu.1114. PMID 11317354. 
• "A role for MLH3 in hereditary nonpolyposis colorectal cancer". Nature Genetics 29 (2): 137–8. Oct 2001. doi:10.1038/ng1001-137. PMID 11586295. 
• "The DNA mismatch-repair MLH3 protein interacts with MSH4 in meiotic cells, supporting a role for this MutL homolog in mammalian meiotic recombination". Human Molecular Genetics 11 (15): 1697–706. Jul 2002. doi:10.1093/hmg/11.15.1697. PMID 12095912. 
• "Little evidence for involvement of MLH3 in colorectal cancer predisposition". International Journal of Cancer 106 (2): 292–6. Aug 2003. doi:10.1002/ijc.11218. PMID 12800209. 
• "Extreme heterogeneity in the molecular events leading to the establishment of chiasmata during meiosis i in human oocytes". American Journal of Human Genetics 76 (1): 112–27. Jan 2005. doi:10.1086/427268. PMID 15558497. 
• "Expression of the MutL homologue hMLH3 in human cells and its role in DNA mismatch repair". Cancer Research 65 (23): 10759–66. Dec 2005. doi:10.1158/0008-5472.CAN-05-2528. PMID 16322221. 
• "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research 16 (1): 55–65. Jan 2006. doi:10.1101/gr.4039406. PMID 16344560. 
• "MLH3 mutation in endometrial cancer". Cancer Research 66 (15): 7502–8. Aug 2006. doi:10.1158/0008-5472.CAN-06-0248. PMID 16885347. 
• "Mutation screening of mismatch repair gene Mlh3 in familial esophageal cancer". World Journal of Gastroenterology 12 (33): 5281–6. Sep 2006. doi:10.3748/wjg.v12.i33.5281. PMID 16981255. 
• "Conditional nuclear localization of hMLH3 suggests a minor activity in mismatch repair and supports its role as a low-risk gene in HNPCC". Oncology Reports 17 (2): 351–4. Feb 2007. doi:10.3892/or.17.2.351. PMID 17203173. 
• "Mutations affecting a putative MutLalpha endonuclease motif impact multiple mismatch repair functions". DNA Repair 6 (10): 1463–70. Oct 2007. doi:10.1016/j.dnarep.2007.04.013. PMID 17567544.