Stress Marks on the Genome: Use or Lose?

Abstract

Oxidative stress and the resulting damage to DNA are inevitable consequence of endogenous physiological processes further amplified by cellular responses to environmental exposures. If left unrepaired, oxidative DNA lesions can block essential processes such as transcription and replication or can induce mutations. Emerging data also indicate that oxidative base modifications such as 8-oxoG in gene promoters may serve as epigenetic marks, and/or provide a platform for coordination of the initial steps of DNA repair and the assembly of the transcriptional machinery to launch adequate gene expression alterations. Here, we briefly review the current understanding of oxidative lesions in genome stability maintenance and regulation of basal and inducible transcription.

Keywords: 8-oxoG; DNA damage; DNA repair; epigenetic; gene expression; helicase; oxidative stress; replication.

Figure 1

Mechanisms of oxidative-stress-induced genetic and epigenetic alterations. Damage to DNA bases due to oxidative stress induced from the plethora of extracellular and intracellular factors is deleterious, leading to stalled replication forks and mutations. Mammalian cells utilize the base excision repair (BER) pathway alone and in concert with various replication restart mechanisms to get rid of oxidative lesions and ensure faithful duplication of genome. Genetic response to oxidative stress involves alteration in gene expression by both the classical gene regulatory mechanisms and by epigenetic processes. Classical gene regulation implicates transcription-factor based gene regulation to influence gene transcription. Epigenetic mechanisms are those that do not involve changes in the genome sequence, but rather in nuclear architecture, chromosome conformation, and histone and DNA modifications. For example, epigenetic involvement of ROS has been attributed to oxidative conversion of 5-mC to 5-hmC. Oxidative conversion of G to 8-oxoG at the promoter regions activates expression of redox-regulated genes suggesting that oxidative base modification may also represent an epigenetic mark serving as sensors of oxidative stress. Involvement of DNA repair (largely BER) in coordinating the gene regulatory response to oxidative stress is indicated by dashed arrow.

Figure 2

The influence of guanine oxidation at the promoter region on gene expression. Reactive oxygen species (ROS) induces oxidation of guanine to 8-oxoG. Gene promoters are enriched in guanine and sequence motifs prone to form G4 DNA structures. Formation of 8-oxoG is also shown to induce critical topological changes in DNA structure. Binding of 8-oxoG by BER proteins may facilitate the site-specific recruitment of specific transcription factors, chromatin remodelers and other accessory factors (shown as ??). These factors likely work in concert to repair the oxidative base lesion (shown by green) and activate transcription of redox-regulated genes for an adequate cellular response.