Mismatch repair: praying for genome stability

For the reader who believes that only computers can faithfully duplicate gigabits of information, some insights into his or her own biology will be revealing. Just as he or she reads this Primer, billions of his or her cells prepare for division by replicating the six billion or so DNA nucleotides of their diploid genomes, each cell typically making not more than a single mistake. This extraordinary precision is critical for maintaining the health of an organism, as a persisting misincorporated nucleotide results in a mutation when copied during the next round of replication. If present in a growth-controlling gene, this mutation might trigger the cellular derailment that underlies the development of cancer. Avoiding persistent misincorporations is crucial not only in somatic cells, but also in germ-line cells, where mutations may introduce hereditary defects into the species. So what are the cellular tools that push replicational mutagenesis down to its almost unimaginably low rate? This cellular machinery acts at three stages. First comes the rigorous nucleotide selectivity of the replicative DNA polymerases, followed secondly by the removal of most inadvertent incorporations by the proofreading functions associated with the polymerases. The resulting misincorporation rate of 10 per duplicated nucleotide would already seem to be an unprecedented accuracy for any enzyme. However, the ensuing rate of mutagenesis would still be far too high to keep the genome in shape. To further eliminate misincorporations, DNA mismatch repair is called into action. This last stage of defense against replicationassociated mutations entered the spotlight in 1993, when inherited defects in mismatch repair were associated with a cancer predisposition syndrome called hereditary nonpolyposis colorectal cancer. In addition, a number of sporadic cancers have also been associated with defects in mismatch repair. DNA mismatch repair has been studied in bacteria for over two decades, so prokaryotes have provided a paradigm to guide research in yeast, plants and mammals. Molecular and mechanistic insights into mismatch repair have emerged from studies by geneticists, cell biologists, biochemists and X-ray crystallographers. These studies have not only revealed that mismatch repair removes up to 99.9% of mismatches resulting from polymerase errors, but have also uncovered roles for mismatch repair proteins in diverse, seemingly unrelated, DNA-associated metabolic processes.