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  • The EMBO Journal (2006) 25, 4316 - 4325
  • doi:10.1038/sj.emboj.7601320

Published online: 7 September 2006

A novel function of DNA polymerase zeta regulated by PCNA

Matthew R Northam1,a, Parie Garg2,a, Dmitri M Baitin1, Peter MJ Burgers2 and Polina V Shcherbakova1

  1. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
  2. Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO, USA

Correspondence to:

Polina V Shcherbakova, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. Tel.: +1 402 559 7694; Fax: +1 402 559 8270; E-mail: pshcherb@unmc.edu

aThese authors contributed equally to this work.

Received 28 April 2006; Accepted 9 August 2006

DNA polymerase zeta (Polzeta) 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 Polzeta to the primer terminus and regulate the extent of its participation in genome replication are poorly understood. The Polzeta-dependent damage-induced mutagenesis requires monoubiquitination of proliferating cell nuclear antigen (PCNA) that is triggered by exposure to mutagens. We show that Polzeta 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 Polzeta-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 Polzeta, but not for monoubiquitination by the Rad6/Rad18 complex demonstrate a role for PCNA in regulating the mutagenic activity of Polzeta separate from its modification at Lys164.

  • Keywords:

    • DNA polymerase zeta,
    • DNA replication,
    • mutagenesis,
    • PCNA,
    • ubiquitination