Oxidative stress-induced mutagenesis in single-strand DNA occurs primarily at cytosines and is DNA polymerase zeta-dependent only for adenines and guanines.
Localized hyper-mutability caused by accumulation of lesions in persistent single-stranded (ss) DNA has been recently found in several types of cancers. An increase in endogenous levels of reactive oxygen species (ROS) is considered to be one of the hallmarks of cancers. Employing a yeast model system, we addressed the role of oxidative stress as a potential source of hyper-mutability in ssDNA by modulation of the endogenous ROS levels and by exposing cells to oxidative DNA-damaging agents. We report here that under oxidative stress conditions the majority of base substitution mutations in ssDNA are caused by erroneous, DNA polymerase (Pol) zeta-independent bypass of cytosines, resulting in C to T transitions. For all other DNA bases Pol zeta is essential for ROS-induced mutagenesis. The density of ROS-induced mutations in ssDNA is lower, compared to that caused by UV and MMS, which suggests that ssDNA could be actively protected from oxidative damage. These findings have important implications for understanding mechanisms of oxidative mutagenesis, and could be applied to development of anticancer therapies and cancer prevention.
Department of Biochemistry, Winship Cancer Institute, Emory University School of Medicine, 4013 Rollins Research Center, Atlanta, GA 30322, USA, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences (NIH, DHHS), Research Triangle Park, NC 27709, USA and Department of Radiation Oncology, Emory University School of Medicine, 4013 Rollins Research Center, Atlanta, GA 30322, USA.
Natalya P
NP
Degtyareva
Lanier
L
Heyburn
Joan
J
Sterling
Michael A
MA
Resnick
Dmitry A
DA
Gordenin
Paul W
PW
Doetsch
D000225:Adenine / Q000737:chemistry; D003596:Cytosine / Q000737:chemistry*; D004247:DNA / Q000096:biosynthesis; D004277:DNA, Single-Stranded / Q000737:chemistry* / Q000187:drug effects; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism / Q000502:physiology; D006147:Guanine / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000633:toxicity; D016296:Mutagenesis; D018384:Oxidative Stress; D010269:Paraquat / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D004718:Saccharomycetales / Q000235:genetics
D004277:DNA, Single-Stranded; D017382:Reactive Oxygen Species; D006147:Guanine; D003596:Cytosine; D004247:DNA; D006861:Hydrogen Peroxide; C425929:DNA polymerase zeta; D004259:DNA-Directed DNA Polymerase; D000225:Adenine; D010269:Paraquat