Replication errors: cha(lle)nging the genome.

Abstract

Since the discovery of a link between the malfunction of post-replicative mismatch correction and hereditary non-polyposis colon cancer, the study of this complex repair pathway has received a great deal of attention. Our understanding of the mammalian system was facilitated by conservation of the main protagonists of this process from microbes to humans. Thus, biochemical experiments carried out with Escherichia coli extracts helped us to identify functional human homologues of the bacterial mismatch repair proteins, while the genetics of Saccharomyces cerevisiae aided our understanding of the phenotypes of human cells deficient in mismatch correction. Today, mismatch repair is no longer thought of solely as the mechanism responsible for the correction of replication errors, whose failure demonstrates itself in the form of a mutator phenotype and microsatellite instability. Malfunction of this process has been implicated also in mitotic and meiotic recombination, drug and ionizing radiation resistance, transcription-coupled repair and apoptosis. Elucidation of the roles of mismatch repair proteins in these transduction pathways is key to our understanding of the role of mismatch correction in human cancer. However, in order to unravel all the complexities involved in post-replicative mismatch correction, we need to know the cast and the roles of the individual players. This brief treatise provides an overview of our current knowledge of the biochemistry of this process.