Evolving Views of DNA

which genetic information is replicated depends on the ability of polymerases to select correct nucleotides— rather than incorrect and/or damaged nucleotides—for incorporation without adding or deleting nucleotides. Polymerase selectivity is the prime determinant of fidelity both at the replication fork and during synthesis to repair DNA damage generated by endogenous cellular metabolism or exposure to the environment (Fried berg et al. 2006). In many organisms, fidelity can be in creased by exonucleolytic proofreading of mismatches during replication and by DNA mismatch repair (MMR) (for review, see Kunkel and Erie 2005; Iyer et al. 2006; Hsieh and Yamane 2008). Certain proteins involved in MMR also can also signal for DNA-damage responses, prevent homologous recombination, promote meiotic re combination, modulate somatic hyper mu tation of im muno glob ulin genes, or even stabilize certain misaligned repetitive DNA sequences. When DNA damage is not removed before replication, helix-distorting lesions can impede replication fork progression. In such circumstances, cell survival can be enhanced by specialized DNA transactions, some of which can be mutagenic via translesion DNA synthesis (Jansen et al. 2007; Yang and Woodgate 2007; Chang and Cimprich 2009). Con sidered here is the amazing diversity of evolutionarily conserved DNA polymerases involved in these transactions, many of which have been discovered relatively recently. Empha sis is on their fidelity and on the contributions of proofreading and MMR to replication fidelity, which can vary over a much wider range than was appreciated even a decade ago. MULTIPLE POLYMERASES WITH MULTIPLE OVERLAPPING FUNCTIONS