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Molecular and Cellular Biology, September 2008, p. 5432-5445, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00307-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Chronic Oxidative DNA Damage Due to DNA Repair Defects Causes Chromosomal Instability in Saccharomyces cerevisiae{triangledown} ,{dagger}

Natalya P. Degtyareva,1,2 Lingling Chen,1 Piotr Mieczkowski,3 Thomas D. Petes,3 and Paul W. Doetsch1,2,4*

Department of Biochemistry,1 Winship Cancer Institute,2 Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia 30322,4 Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina 277103

Received 22 February 2008/ Returned for modification 28 March 2008/ Accepted 24 June 2008

Oxidative DNA damage is likely to be involved in the etiology of cancer and is thought to accelerate tumorigenesis via increased mutation rates. However, the majority of malignant cells acquire a specific type of genomic instability characterized by large-scale genomic rearrangements, referred to as chromosomal instability (CIN). The molecular mechanisms underlying CIN are not entirely understood. We utilized Saccharomyces cerevisiae as a model system to delineate the relationship between genotoxic stress and CIN. It was found that elevated levels of chronic, unrepaired oxidative DNA damage caused chromosomal aberrations at remarkably high frequencies under both selective and nonselective growth conditions. In this system, exceeding the cellular capacity to appropriately manage oxidative DNA damage resulted in a "gain-of-CIN" phenotype and led to profound karyotypic instability. These results illustrate a novel mechanism for genome destabilization that is likely to be relevant to human carcinogenesis.

* Corresponding author. Mailing address: Dept. of Biochemistry, Emory University School of Medicine, 4013 Rollins Research Center, Atlanta, GA 30322. Phone: (404) 727-0409. Fax: (404) 727-3231. E-mail: medpwd{at}emory.edu

{triangledown} Published ahead of print on 30 June 2008.

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

Molecular and Cellular Biology, September 2008, p. 5432-5445, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00307-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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