Evolving views of DNA replication (in)fidelity.

"It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material" (Watson and Crick 1953). In the years since this remarkable understatement, we have come to realize the enormous complexity of the cellular machinery devoted to replicating DNA with the accuracy needed to maintain genetic information over many generations, balanced by the emergence of mutations on which selection can act. This complexity is partly based on the need to remove or tolerate cytotoxic and mutagenic lesions in DNA generated by environmental stress. Considered here is the fidelity with which undamaged and damaged DNA is replicated by the many DNA polymerases now known to exist. Some of these seriously violate Watson-Crick base-pairing rules such that, depending on the polymerase, the composition and location of the error, and the ability to correct errors (or not), DNA synthesis error rates can vary by more than a millionfold. This offers the potential to modulate rates of point mutations over a wide range, with consequences that can be either deleterious or beneficial.