title: Oxidative stress at low levels can induce clustered DNA lesions leading to NHEJ mediated mutations.
abstract: DNA damage and mutations induced by oxidative stress are associated with various different human pathologies including cancer. The facts that most human tumors are characterized by large genome rearrangements and glutathione depletion in mice results in deletions in DNA suggest that reactive oxygen species (ROS) may cause gene and chromosome mutations through DNA double strand breaks (DSBs). However, the generation of DSBs at low levels of ROS is still controversial. In the present study, we show that H2O2 at biologically-relevant levels causes a marked increase in oxidative clustered DNA lesions (OCDLs) with a significant elevation of replication-independent DSBs. Although it is frequently reported that OCDLs are fingerprint of high-energy IR, our results indicate for the first time that H2O2, even at low levels, can also cause OCDLs leading to DSBs specifically in G1 cells. Furthermore, a reverse genetic approach revealed a significant contribution of the non-homologous end joining (NHEJ) pathway in H2O2-induced DNA repair & mutagenesis. This genomic instability induced by low levels of ROS may be involved in spontaneous mutagenesis and the etiology of a wide variety of human diseases like chronic inflammation-related disorders, carcinogenesis, neuro-degeneration and aging.
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, Chapel Hill, NC 27599, USA.
authors.forename: Vyom
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, Chapel Hill, NC 27599, USA.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Collins
authors.affiliation: Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Ting-Huei
authors.initials: TH
authors.lastname: Chen
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, Chapel Hill, NC 27599, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Herr
authors.affiliation: Department of Radiation Genetics, Graduate School of Medicine, Kyoto 606-8501, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, Chapel Hill, NC 27599, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, Chapel Hill, NC 27599, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D002460:Cell Line; D002645:Chickens; D004249:DNA Damage / Q000502:physiology*; D059766:DNA End-Joining Repair / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000633:toxicity; D016296:Mutagenesis / Q000502:physiology*; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000502:physiology*
chemical_list: D016877:Oxidants; D006861:Hydrogen Peroxide
keywords: NHEJ; clustered DNA lesions; double strand breaks; mutations; oxidative stress