Expression of the MutL Homologue hMLH3 in Human Cells and its Role in DNA Mismatch Repair

摘要: The human mismatch repair (MMR) proteins hMLH1 and hPMS2 function in MMR as a heterodimer. Cells lacking either protein have strong mutator phenotype display microsatellite instability, yet mutations the gene account for approximately 50% of hereditary nonpolyposis colon cancer families, whereas are substantially less frequent penetrant. Similarly, mouse model, Mlh1-/- animals highly prone present with gastrointestinal tumors at an early age, Pms2-/- mice succumb to much later life do not tumors. This evidence suggested that MLH1 might functionally interact another MutL homologue, which compensates, least part, deficiency PMS2. Sterility Mlh1-/-, Pms2-/-, Mlh3-/- implicated Mlh1/Pms2 Mlh1/Mlh3 heterodimers meiotic recombination. We now show hMLH1/hMLH3 heterodimer, hMutLgamma, can also assist base-base mismatches single extrahelical nucleotides vitro. Analysis hMLH3 expression cell lines indicated levels vary independently hMLH1. If participates vivo, its partial redundancy hPMS2, coupled fluctuating hMLH3, may help explain low penetrance families.