Y-family DNA polymerases in mammalian cells

Abstract

Eukaryotic genomes are replicated with high fidelity to assure the faithful transmission of genetic information from one generation to the next. The accuracy of replication relies heavily on the ability of replicative DNA polymerases to efficiently select correct nucleotides for the polymerization reaction and, using their intrinsic exonuclease activities, to excise mistakenly incorporated nucleotides. Cells also possess a variety of specialized DNA polymerases that, by a process called translesion DNA synthesis (TLS), help overcome replication blocks when unrepaired DNA lesions stall the replication machinery. This review considers the properties of the Y-family (a subset of specialized DNA polymerases) and their roles in modulating spontaneous and genotoxic-induced mutations in mammals. We also review recent insights into the molecular mechanisms that regulate PCNA monoubiquitination and DNA polymerase switching during TLS and discuss the potential of using Y-family DNA polymerases as novel targets for cancer prevention and therapy.

Fig. 1

The structural domains of the Y-family polymerases. Protein size is represented proportionately. BRCT BRCA1 C terminus-like domain, UBM ubiquitin binding motif, UBZ ubiquitin binding zinc finger motif, PAD polymerase associated domain, NLS nuclear localization signal, PIP PCNA interaction peptide

Fig. 2

A model depicting the regulation of PCNA monoubiquitination and TLS polymerases switching at sites of stalled replication. Following DNA damage treatments, RPA binds to ssDNA at sites of stalled forks, in which RPA targets Rad18 to its sites of action [168] and stimulate PCNA monoubiquitination. Monoubiquitination PCNA enables removal of replication polymerase and recruitment of TLS polymerases to the primer terminus. This process is regulated by Chk1 but not ATR. Claspin, which is stabilized by Chk1, regulates the binding of the ubiquitin ligase Rad18 to chromatin [173]. Meanwhile, UV inactivates USP1 to stimulate accumulation of monoubiquitinated PCNA [174]. Moreover, Rad18/Rad6 complex can also monoubiquitinate some other proteins at sites of stalled replication forks [179, 180], which may recruit TLS polymerases in parallel with monoubiquitinated PCNA. Furthermore, monoubiquitinated Y-family polymerases may contribute to regulation of their compartmentalization in or out of replication factories [29]