On the Fidelity of DNA Replication

Abstract

To maintain species identity, DNA replication must be an exceptionally faithful process. The only inaccuracies tolerated would be those infrequent mutations that provide for species diversity. On the basis of spontaneous mutation rates in prokaryotic and eukaryotic cells, it is usually estimated that stable misincorporation of a base during DNA replication occurs with a frequency of 10−8–10−11/bp synthesized (Drake 1969). This accuracy appears to be achieved by a multistep process (Table 1). First, the difference in free energy (−ΔG) for correct over incorrect Watson-Crick base pairings results from little more than one hydrogen bond (2–3 kcal). This accounts for an error rate of approximately 10−2 (Mildvan 1974; Loeb et al. 1974; Hopfield 1974). Second, DNA polymerases themselves participate in base selection, reducing the error rate to values approaching 10−5 (Loeb 1974). Such error prevention could result from different types of enzyme-template-substrate interaction (Table 1). Alternatively, prokaryotic DNA polymerases (Komberg 1974)...