|MutL homolog 1|
|Symbols||; COCA2; FCC2; HNPCC; HNPCC2; hMLH1|
|RNA expression pattern|
MutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) is a protein that in humans is encoded by the MLH1 gene located on Chromosome 3. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH11 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae.
This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). It is a human homolog of the E. coli DNA mismatch repair gene, mutL, which mediates protein-protein interactions during mismatch recognition, strand discrimination, and strand removal. Defects in MLH1 are associated with the microsatellite instability (MSI) observed in HNPCC. Alternatively spliced transcript variants encoding different isoforms have been described, but their full-length natures have not been determined.
In addition to its role in DNA mismatch repair, MLH1 protein is also involved in meiotic crossing over. MLH1 forms a heterodimer with MLH3 that appears to be necessary for oocytes to progress through metaphase II of meiosis. Female and male MLH1(-/-) mutant mice are infertile, and sterility is associated with a reduced level of chiasmata. During spermatogenesis in MLH1(-/-) mutant mice chromosomes often separate prematurely and there is frequent arrest in the first division of meiosis. In humans, a common variant of the MLH1 gene is associated with increased risk of sperm damage and male infertility.
MLH1 protein appears to localize to sites of crossing over in meiotic chromosomes. 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 an 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, MLH1 forms a heterodimer with MLH3. 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.
MLH1 has been shown to interact with:
- "Entrez Gene: MLH1 mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli)".
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- FAQs on HNPCC from the National Institute of Health
- GeneReviews/NCBI/NIH/UW entry on Lynch syndrome
- MLH1 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
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