The fidelity with which genetic information is replicated depends on the ability of DNA polymerases to select correct nucleotides rather than incorrect or damaged nucleotides for incorporation, without adding or deleting nucleotides. Polymerase selectivity is a major determinant of fidelity both at the replication fork and during synthesis to repair DNA damage. Mismatches generated during DNA chain elongation can be removed by 3′-exonuclease activity of the major replicative polymerases, thereby enhancing fidelity. If a mismatch escapes proofreading, DNA mismatch repair (MMR) can excise the replication error in the nascent strand and replace it with the correct sequence. Under normal circumstances, nucleotide selectivity, proofreading and MMR operate in series to replicate the genome with very high fidelity, thereby contributing to low spontaneous mutation rates (). Consequently, defects in any of these three processes can increase mutation rates, and this mutator phenotype can potentially be a driving force for cancer.
Fig. 1 Contribution of nucleotide selectivity, proofreading and DNA mismatch repair to DNA replication fidelity. The figure depicts the wide-ranging contributions of three major processes that act in series to determine DNA replication fidelity. The colored (more ...)
When lesions in DNA generated by endogenous cellular metabolism or exposure to chemical or physical insults from the external environment are not removed prior to replication, they sometimes distort the DNA helix and impede replication fork progression. In such circumstances, cell survival can be enhanced by several different DNA transactions. One such transaction is translesion synthesis (TLS), a process that allows lesions to be tolerated until they can be repaired. TLS is catalyzed by highly specialized, exonuclease-deficient DNA polymerases whose catalytic properties, including fidelity, are quite different than those that perform the bulk of replication. This review focuses on the eukaryotic replicative and TLS DNA polymerases that have critical roles in accurately and efficiently replicating the nuclear genome. Readers interested in DNA synthesis catalyzed in mitochondria, or in additional DNA polymerases that function in DNA repair, can consult other reviews [1
]. Emphasis here is on the fidelity of replication, how it can be reduced to result in mutator phenotypes associated with cancer, and differences in replication error specificity that may have diagnostic value when considering replication infidelity as a source of point mutations arising in tumor cells.