Chronic oxidative DNA damage due to DNA repair defects causes chromosomal instability in Saccharomyces cerevisiae.
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.
Degtyareva
Natalya P
NP
Dept. of Biochemistry, Emory University School of Medicine, 4013 Rollins Research Center, Atlanta, GA 30322, USA. medpwd@emory.edu
Chen
Lingling
L
Mieczkowski
Piotr
P
Petes
Thomas D
TD
Doetsch
Paul W
PW
D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D015825:Chromosomes, Fungal / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004171:Diploidy; D016166:Free Radical Scavengers / Q000378:metabolism; D020440:Gene Duplication; D017930:Genes, Reporter; D006238:Haploidy; D008954:Models, Biological; D009693:Nucleic Acid Hybridization; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors
D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species