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.

The Role of Dietary Antioxidants in the Pathogenesis of Neurodegenerative Diseases and Their Impact on Cerebral Oxidoreductive Balance

“…Some of the most dangerous types of cell damage are caused by reactions between ROS and nuclear DNA. Such interactions may lead to single or double ruptures in the DNA, the latter being particularly toxic for a cell and capable of directly triggering cell death; they can also lead to the emergence of networking bonds or modifications to nitrogen bases [48,49]. Furthermore, attention has been drawn to damaged mitochondrial DNA (mtDNA), which may be a significant element in the etiology of many diseases and senile conditions [50].…”

Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice

“…2d). Interestingly, Sharma et al have proposed that ROS-induced damage can cause oxidatively induced clustered DNA lesions that lead to double strand breaks and deletions caused by error-prone repair by the nonhomologous end-joining (NHEJ) pathway 41 . It is therefore possible that the co-occurrence of SNV signature 18 and signature INDEL A is related to relatively higher levels of ROS induced by gamma rays, but further detailed studies would be required to confirm this association.…”

Genes lost during the transition from land to water in cetaceans highlight genomic changes involved in aquatic adaptations

“…POLM encodes the DNA polymerase Polµ, which plays an integral role in DNA damage repair (64). The most severe type of DNA damage caused by ROS is a DNA double strand break (65). One mechanism to repair double strand breaks is non-homologous end joining (NHEJ), a process that ligates DNA strands without requiring a homologous template and re-synthesizes missing DNA bases by DNA polymerases.…”