ABSTRACT
Cells have evolved efficient, integrated pathways for detecting and avoiding genetic catastrophe. Events that have the potential to develop into such a fate include genomic lesions resulting from exposure to DNA damaging agents, physical and chemical stress, aberrant recombination events or replication-induced DNA biosynthetic errors. Left unresolved, such damage might result in mutability, genomic instability and/or eventual cell death. Specialized DNA repair pathways-nucleotide excision repair, base excision repair, the recombination pathways (nonhomologous end joining and double strand break repair), and mismatch repair (MMR)—have evolved to correct these errors. Typically, specific damage-recognition proteins initiate the repair process followed by the coordinated assembly of multiprotein complexes that repair the damage. Loss of MMR results in a mutator phenotype and is closely associated with hereditary nonpolyposis colorectal cancer (HNPCC) (1,2). Understanding the basis for this link has propelled the research on MMR and a considerable genetic, structural, and biochemical knowledge has accumulated. However, the precise mechanism of MMR is fervently debated. Here, we review the biochemical history of the MMR field and the various mechanisms proposed, and discuss the mechanism that appears most consistent with the biochemical observations.
