Subunit sharing among high- and low-fidelity DNA polymerases

To preserve genetic information through generations, DNA must be duplicated with precision, and thus DNA polymerases (Pols) that replicate chromosomes are highly accurate. However, DNA is constantly bombarded by damage and undergoing repair, and, if the replication fork encounters a damaged base before repair, highly accurate replicases stall and cannot continue fork progression. All cells contain specialized translesion (TLS) Pols that have low accuracy but can extend DNA over template lesions (1, 2). Although some TLS Pols have evolved to insert the correct nucleotide opposite particular lesions, they can also be mutagenic by inserting an incorrect base. The conservation of TLS Pols in all cells suggests that single-base mutations may offer a better outcome than fork collapse, cell death, or recombination that results in gross chromosome abnormalities. However, there has been longstanding confusion regarding the participation of the high-fidelity eukaryotic replicase Pol δ in the mutagenic TLS process, a dilemma that is largely resolved by data presented in PNAS showing sharing of subunits between Pol δ and TLS Pol ζ (3). TLS can be error-free or error-prone, and can thus prevent or contribute to cancer. Yeast have TLS Pols η, ζ, and Rev1, and mammalian cells contain yet other TLS Pols (1). TLS Pol η can be mutagenic but is error-free in extending DNA over T-T cis-syn dimers, a common UV lesion, and mutations in Pol η confer sensitivity to UV radiation and underlie cancer disposition in the variant form of Xeroderma pigmentosum syndrome. Pol ζ is not itself error-prone, but it promotes mutations by extending DNA chains from mispaired bases after a low-fidelity Pol inserts the incorrect nucleotide across from a template lesion (4). Genetic data show that the high-fidelity replicase Pol δ also participates in error-prone DNA repair, particularly that induced by DNA damaging agents …