Shifting replication between IInd, IIIrd, and IVth gears

Abstract

We used to think cells could get by with just a few DNA polymerases. One processive polymerase in Escherichia coli [polymerase III (Pol III)] was needed to make the long trip around the genome, and another one (Pol I) was needed to replace Okazaki fragment primers or damaged nucleotides. This view changed radically after 2 seminal studies by Nelson, Lawrence, and Hinkle (1, 2) in which 2 yeast enzymes, Rev1 and Rev3-Rev7, were found to incorporate nucleosides or polymerize past template sites with missing or damaged bases. These new polymerases helped to explain a rich history of mutational phenomena and led to the realization that organisms have several of these specialized DNA polymerases; E. coli has 3 (Pol II, Pol IV, and Pol V). Yeast have 5. Humans have >10. Each appears specialized for polymerization through different structural classes of DNA damage (3). Although there is no shortage of polymerases from which to choose, the question of how and when they act in the cell has proved difficult to answer. Perhaps this is not so surprising when one considers how long they went unnoticed. A novel and provocative function is proposed in this issue of PNAS in a study by Indiani et al. (4). They demonstrate that either Pol II or Pol IV can replace Pol III at an active replication fork. When this occurs, the new polymerases shift the replisome into a “lower gear,” reducing the speed of replication. That observation complements a recent in vivo study by Uchida et al. (5) in which the rate of DNA synthesis could be slowed or inhibited by overexpression of Pol IV. Indiani et al. (4) found that this was also true when Pol II was overexpressed. Both studies speculate that the slower Pol II or Pol IV replisomes are biologically relevant, serving a checkpoint-like function that allows more time for damaged DNA to be repaired before it is replicated (Fig. 1A).