20 DNA Polymerases and the Fidelity of DNA Replication

Abstract

The spontaneous mutation rate in normal human cells is estimated to be 10⁻⁹ to 10⁻¹¹ (Drake et al. 1998; Loeb 2001), suggesting that eukaryotic chromosomal DNA replication is highly accurate. Accurate replication depends on multiple DNA transactions. Several DNA repair pathways remove DNA lesions generated by endogenous cellular metabolism or environmental agents, thus providing clean substrates for the replication machinery. Accurate copying of undamaged DNA templates results from the high nucleotide selectivity of the major replicative DNA polymerases, the ability of their intrinsic exonucleases to excise mismatches they create, and the ability of the DNA mismatch repair machinery to remove mismatches not excised by proofreading. When occasional unrepaired DNA lesions or other circumstances stall replication, other processes, including translesion DNA synthesis involving specialized DNA polymerases, help to overcome replication blocks. Malfunction of these processes can reduce replication fidelity and genome stability, with important consequences for human disease.

EUKARYOTIC DNA POLYMERASES AND THEIR FUNCTIONS
Both eukaryotic and prokaryotic genomes encode multiple DNA polymerases to conduct these many transactions (for review, see Shcherbakova et al. 2003; Bebenek and Kunkel 2004). These polymerases are classified into seven different families based on the primary sequences of their catalytic subunits. Representatives of five of these seven families are found in eukaryotic cells. For example, in humans, a total of 17 enzymes capable of polymerizing DNA have been described to date, and homologs of many of these enzymes are present in other eukaryotes, e.g., Saccharomyces cerevisiae (Table 1). Family A includes DNA polymerases that are homologous...