DNA polymerase ζ in DNA replication and repair

Here, we survey the diverse functions of DNA polymerase zeta (pol zeta) in eukaryotes. In mammalian cells, REV3L (3130 residues) is the largest catalytic subunit of the DNA polymerases. The orthologous subunit in yeast is Rev3p. Pol zeta also includes REV7 subunits (encoded by Rev7 in yeast and MAD2L2 in mammalian cells) and two subunits shared with the replicative DNA polymerase, pol delta. Pol zeta is used in response to circumstances that stall DNA replication forks in both yeast and mammalian cells. The best-examined situation is translesion synthesis at sites of covalent DNA lesions such as UV radiation-induced photoproducts. We also highlight recent evidence that uncovers various roles of pol zeta that extend beyond translesion synthesis. For instance, pol zeta is also employed when the replisome operates sub-optimally or at difficult-to-replicate DNA sequences. Pol zeta also participates in repair by microhomology mediated break-induced replication. A rev3 deletion is tolerated in yeast but Rev3l disruption results in embryonic lethality in mice. Inactivation of mammalian Rev3l results in genomic instability and invokes cell death and senescence programs. Targeting of pol zeta function may be a useful strategy in cancer therapy, although chromosomal instability associated with pol zeta deficiency must be considered.