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Molecular and Cellular Biology, March 2009, p. 1212-1221, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01499-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Transition of Closely Opposed Lesions to Double-Strand Breaks during Long-Patch Base Excision Repair Is Prevented by the Coordinated Action of DNA Polymerase {delta} and Rad27/Fen1{triangledown} ,{dagger}

Wenjian Ma,1 Vijayalakshmi Panduri,1 Joan F. Sterling,1 Bennett Van Houten,1,2 Dmitry A. Gordenin,1,{ddagger}* and Michael A. Resnick1,{ddagger}*

Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709,1 Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 152132

Received 25 September 2008/ Returned for modification 22 October 2008/ Accepted 4 December 2008

DNA double-strand breaks can result from closely opposed breaks induced directly in complementary strands. Alternatively, double-strand breaks could be generated during repair of clustered damage, where the repair of closely opposed lesions has to be well coordinated. Using single and multiple mutants of Saccharomyces cerevisiae (budding yeast) that impede the interaction of DNA polymerase {delta} and the 5'-flap endonuclease Rad27/Fen1 with the PCNA sliding clamp, we show that the lack of coordination between these components during long-patch base excision repair of alkylation damage can result in many double-strand breaks within the chromosomes of nondividing haploid cells. This contrasts with the efficient repair of nonclustered methyl methanesulfonate-induced lesions, as measured by quantitative PCR and S1 nuclease cleavage of single-strand break sites. We conclude that closely opposed single-strand lesions are a unique threat to the genome and that repair of closely opposed strand damage requires greater spatial and temporal coordination between the participating proteins than does widely spaced damage in order to prevent the development of double-strand breaks.

* Corresponding author. Mailing address: Chromosome Stability Section, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709. Phone for Michael A. Resnick: (919) 541-4480. Fax: (919) 541-7593. E-mail: resnick{at}niehs.nih.gov. Phone for Dmitry A. Gordenin: (919) 541-5190. Fax: (919) 541-7593. E-mail: gordenin{at}niehs.nih.gov

{triangledown} Published ahead of print on 15 December 2008.

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

{ddagger} D.A.G. and M.A.R. contributed equally to this study.

Molecular and Cellular Biology, March 2009, p. 1212-1221, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01499-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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