Anti-MLH1

DNA-mismatch repair (MMR), a conserved process that involves correcting errors made during DNA synthesis, is crucial to the maintenance of genomic integrity. Lack of a functional DNA-mismatch repair pathway is a common characteristic of several different types of human cancers, either due to an MMR gene mutation or promoter-methylation gene silencing. MLH1 is a human homolog of the E. coli DNA mismatch repair gene mutL, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in hereditary nonpolyposis colon cancer (HNPCC). MLH1 is an integral part of the protein complex responsible for mismatch repair expressed in lymphocytes, heart, colon, breast, lung, spleen, testis, prostate, thyroid and gall bladder, and is methylated in several ovarian tumors. Loss of MLH1 protein expression is associated with a mutated phenotype, microsatellite instability and a predisposition to cancer. In hereditary nonpolyposis colorectal cancer (HNPCC), an autosomal dominant inherited cancer syndrome that signifies a high risk of colorectal and various other types of cancer, the MLH1 gene exhibits a pathogenic mutation. Inactivation of the MLH1 gene causes genome instability and predisposition to cancer. MLH1 also plays a role in meiotic recombination. Control: Appendix, tonsil, mutated and non-mutated colorectal carcinoma. Protein function: Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis. [The UniProt Consortium]