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Molecular and Cellular Biology, October 2009, p. 5316-5326, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.00422-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Polymerase {eta} Translesion Synthesis DNA Polymerase Acts Independently of the Mismatch Repair System To Limit Mutagenesis Caused by 7,8-Dihydro-8-Oxoguanine in Yeast{triangledown} ,{dagger}

Sarah V. Mudrak,1 Caroline Welz-Voegele,2 and Sue Jinks-Robertson1,2*

Department of Molecular Genetics and Microbiology,2 University Program in Genetics and Genomics, Duke University Medical Center, Durham, North Carolina 277101

Received 1 April 2009/ Returned for modification 17 May 2009/ Accepted 19 July 2009

Reactive oxygen species are ubiquitous mutagens that have been linked to both disease and aging. The most studied oxidative lesion is 7,8-dihydro-8-oxoguanine (GO), which is often miscoded during DNA replication, resulting specifically in GC -> TA transversions. In yeast, the mismatch repair (MMR) system repairs GO·A mismatches generated during DNA replication, and the polymerase {eta} (Pol{eta}) translesion synthesis DNA polymerase additionally promotes error-free bypass of GO lesions. It has been suggested that Pol{eta} limits GO-associated mutagenesis exclusively through its participation in the filling of MMR-generated gaps that contain GO lesions. In the experiments reported here, the SUP4-o forward-mutation assay was used to monitor GC -> TA mutation rates in strains defective in MMR (Msh2 or Msh6) and/or in Pol{eta} activity. The results clearly demonstrate that Pol{eta} can function independently of the MMR system to prevent GO-associated mutations, presumably through preferential insertion of cytosine opposite replication-blocking GO lesions. Furthermore, the Pol{eta}-dependent bypass of GO lesions is more efficient on the lagging strand of replication and requires an interaction with proliferating cell nuclear antigen. These studies establish a new paradigm for the prevention of GO-associated mutagenesis in eukaryotes.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, DUMC Box 3020, Duke University Medical Center, Durham, NC 27710. Phone: (919) 681-7273. Fax: (919) 684-2790. E-mail: sue.robertson{at}duke.edu

{triangledown} Published ahead of print on 27 July 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, October 2009, p. 5316-5326, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.00422-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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