DNA polymerases ζ and Rev1 mediate error-prone bypass of non-B DNA structures

Matthew R. Northam, Elizabeth A. Moore, Tony M. Mertz, Sara K. Binz, Carrie M. Stith, Elena I. Stepchenkova, Kathern L. Wendt, Peter M.J. Burgers, Polina V. Shcherbakova

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

DNA polymerase ζ (Pol ζ) and Rev1 are key players in translesion DNA synthesis. The error-prone Pol ζ can also participate in replication of undamaged DNA when the normal replisome is impaired. Here we define the nature of the replication disturbances that trigger the recruitment of error-prone polymerases in the absence of DNA damage and describe the specific roles of Rev1 and Pol ζ in handling these disturbances. We show that Pol ζ/Rev1-dependent mutations occur at sites of replication stalling at short repeated sequences capable of forming hairpin structures. The Rev1 deoxycytidyl transferase can take over the stalled replicative polymerase and incorporate an additional 'C' at the hairpin base. Full hairpin bypass often involves template-switching DNA synthesis, subsequent realignment generating multiply mismatched primer termini and extension of these termini by Pol ζ. The postreplicative pathway dependent on polyubiquitylation of proliferating cell nuclear antigen provides a backup mechanism for accurate bypass of these sequences that is primarily used when the Pol ζ/Rev1-dependent pathway is inactive. The results emphasize the pivotal role of noncanonical DNA structures in mutagenesis and reveal the long-sought-after mechanism of complex mutations that represent a unique signature of Pol ζ.

Original languageEnglish (US)
Pages (from-to)290-306
Number of pages17
JournalNucleic acids research
Volume42
Issue number1
DOIs
StatePublished - Jan 7 2014

ASJC Scopus subject areas

  • Genetics

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    Northam, M. R., Moore, E. A., Mertz, T. M., Binz, S. K., Stith, C. M., Stepchenkova, E. I., Wendt, K. L., Burgers, P. M. J., & Shcherbakova, P. V. (2014). DNA polymerases ζ and Rev1 mediate error-prone bypass of non-B DNA structures. Nucleic acids research, 42(1), 290-306. https://doi.org/10.1093/nar/gkt830