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Nucleic Acids Research Advance Access originally published online on September 13, 2006
Nucleic Acids Research 2006 34(17):4731-4742; doi:10.1093/nar/gkl465
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Nucleic Acids Research, 2006, Vol. 34, No. 17 4731-4742
Published by Oxford University Press 2006

Nucleic Acid Enzymes

The fidelity of DNA synthesis by yeast DNA polymerase zeta alone and with accessory proteins

Xuejun Zhong, Parie Garg2, Carrie M. Stith2, Stephanie A. Nick McElhinny, Grace E. Kissling1, Peter M. J. Burgers2 and Thomas A. Kunkel*

Laboratory of Molecular Genetics and Laboratory of Structural Biology, National Institute of Environmental Health Sciences, NIH, DHHS Research Triangle Park, NC 27709, USA 1 Biostatistics Branch, National Institute of Environmental Health Sciences, NIH, DHHS Research Triangle Park, NC 27709, USA 2 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine St Louis, MO 63110, USA

*To whom correspondence should be addressed at: Bldg 101, Room E342B, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709-2233, USA. Tel: +1 919 541 2644; Fax: +1 919 541 7613; Email: kunkel{at}niehs.nih.gov

Received May 2, 2006. Revised June 15, 2006. Accepted June 15, 2006.

DNA polymerase zeta (pol {zeta}) participates in several DNA transactions in eukaryotic cells that increase spontaneous and damage-induced mutagenesis. To better understand this central role in mutagenesis in vivo, here we report the fidelity of DNA synthesis in vitro by yeast pol {zeta} alone and with RFC, PCNA and RPA. Overall, the accessory proteins have little effect on the fidelity of pol {zeta}. Pol {zeta} is relatively accurate for single base insertion/deletion errors. However, the average base substitution fidelity of pol {zeta} is substantially lower than that of homologous B family pols {alpha}, {delta} and {varepsilon}. Pol {zeta} is particularly error prone for substitutions in specific sequence contexts and generates multiple single base errors clustered in short patches at a rate that is unprecedented in comparison with other polymerases. The unique error specificity of pol {zeta} in vitro is consistent with Pol {zeta}-dependent mutagenic specificity reported in vivo. This fact, combined with the high rate of single base substitution errors and complex mutations observed here, indicates that pol {zeta} contributes to mutagenesis in vivo not only by extending mismatches made by other polymerases, but also by directly generating its own mismatches and then extending them.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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