A novel function of DNA polymerase ζ regulated by PCNA

DNA polymerase zeta (Pol zeta) participates in translesion DNA synthesis and is involved in the generation of the majority of mutations induced by DNA damage. The mechanisms that license access of Pol zeta to the primer terminus and regulate the extent of its participation in genome replication are poorly understood. The Pol zeta-dependent damage-induced mutagenesis requires monoubiquitination of proliferating cell nuclear antigen (PCNA) that is triggered by exposure to mutagens. We show that Pol zeta contributes to DNA replication and causes mutagenesis not only in response to DNA damage but also in response to malfunction of normal replicative machinery due to mutations in replication genes. These replication defects lead to ubiquitination of PCNA even in the absence of DNA damage. Unlike damage-induced mutagenesis, the Pol zeta-dependent spontaneous mutagenesis in replication mutants is reduced in strains defective in both ubiquitination and sumoylation of Lys164 of PCNA. Additionally, studies of a PCNA mutant defective for functional interactions with Pol zeta, but not for monoubiquitination by the Rad6/ Rad18 complex demonstrate a role for PCNA in regulating the mutagenic activity of Pol zeta separate from its modification at Lys164.