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J. Biol. Chem., Vol. 279, Issue 21, 22585-22594, May 21, 2004

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Spontaneous DNA Damage in Saccharomyces cerevisiae Elicits Phenotypic Properties Similar to Cancer Cells^*

Barbara A. Evert¶, Tiffany B. Salmon¶, Binwei Song, Liu Jingjing||, Wolfram Siede||, and Paul W. Doetsch**

From the Department of Biochemistry, Graduate Program in Genetics and Molecular Biology, ^**Department of Biochemistry and Division of Cancer Biology, and Department of Radiation Oncology, School of Medicine, Emory University, Atlanta, Georgia, 30322 and the ^||Department of Cell Biology and Genetics, University of North Texas Health Science Center, Fort Worth, Texas 76107

To determine the spectrum of effects elicited by specific levels of spontaneous DNA damage, a series of isogenic Saccharomyces cerevisiae strains defective in base excision repair (BER) and nucleotide excision repair (NER) were analyzed. In log phase of growth, when compared with wild type (WT) or NER-defective cells, BER-defective cells and BER/NER-defective cells possess elevated levels of unrepaired, spontaneous oxidative DNA damage. This system allowed establishment of a range of 400 to 1400 Ntg1p-recognized DNA lesions per genome necessary to provoke profound biological changes similar in many respects to the phenotypic properties of cancer cells. The BER/NER-defective cells are genetically unstable, exhibiting mutator and hyper-recombinogenic phenotypes. They also exhibit aberrations in morphology, DNA content, and growth characteristics compared with WT, BER-defective, and NER-defective cells. The BER/NER-defective cells also possess increased levels of intracellular reactive oxygen species, activate the yeast checkpoint response pathway via Rad53p phosphorylation in stationary phase, and show profound changes in transcription patterns, a subset of which can be ascribed to responses resulting from unrepaired DNA damage. By establishing a relationship between specific levels of spontaneous DNA damage and the ensuing deleterious biological consequences, these yeast DNA excision repair-defective strains are an informative model for gauging the progressive biological consequences of spontaneous DNA damage accumulation and may have relevancy for delineating underlying mechanisms in tumorigenesis.

Received for publication, January 15, 2004 , and in revised form, March 10, 2004.

^* This work was supported by National Institutes of Health Grants ES11163 and CA87381. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Both authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Biochemistry, Rollins Research Center, Rm. 4013, 1510 Clifton Rd., Atlanta, GA 30322. Tel.: 404-727-0409; Fax: 404-727-2618; E-mail: medpwd{at}emory.edu.

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