Oxidative stress-induced mutagenesis in single-strand DNA occurs primarily at cytosines and is DNA polymerase zeta-dependent only for adenines and guanines

Abstract

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.

An engineered cell line lacking OGG1 and MUTYH glycosylases implicates the accumulation of genomic 8-oxoguanine as the basis for paraquat mutagenicity

“…There are several overlapping and cross-talking mechanisms among DNA repair pathways. When SSBs repair intermediates caused by oxidative damage are created and persist into S-phase, they can become DSBs during replication and then require HR or NHEJ to be repaired [13–16]. The present study showed that PQ-induced DSBs were dose-dependent and, therefore, correlated with the level of oxidative stress.…”

“…In addition to BER, oxidative-stress induced DNA lesions can be repaired by nucleotide excision repair (NER) [7, 13, 14]. Both pathways generate single-strand breaks (SSBs) in DNA as repair intermediates.…”

“…Both pathways generate single-strand breaks (SSBs) in DNA as repair intermediates. If the level of lesions is high, or if the repair is happening concurrent with replication, much more lethal double-strand breaks (DSBs) can occur [13–15]. Therefore, when the capacity to repair SSB is exceeded, or is compromised, the survival of the cell depends on its ability to repair DSBs using either homologous recombination (HR) or non-homologous end-joining (NHEJ) [15, 16].…”

Redox regulation of mitophagy in the lung during murine Staphylococcus aureus sepsis

“…This prevents further deleterious ROS production and subsequent damage to DNA, lipids, and other proteins [36]. Here we found that systemic S. aureus sepsis produces lung mitochondrial damage as visualized by cytoplasmic ssDNA [37]. In addition to the removal of these damaged mitochondria, the cell must also replace these organelles in order to restore cellular bioenergetics.…”

Status of Epstein-Barr Virus Coinfection withHelicobacter pyloriin Gastric Cancer

“…Several studies showed that the upregulation of inflammatory cytokines IL1- β , NOS 2, and TNF- α induced methylation [46–49, 51, 52, 263]. H. pylori induces oxidative stress, ROS, and RNS which can cause p53 point mutations [264–267]. Nitric oxide (NO) can cause G:T mismatch during DNA synthesis and eventually results in G:C to A:T base transversion and epigenetic modification of tumorigenic genes (Figure 2) [268, 269].…”