8-Oxoguanine DNA glycosylase 1 (OGG1) initiates the base excision repair pathway by removing one of the most abundant DNA lesions, 8-oxo-7,8-dihydroguanine (8-oxoG). Recent data showed that 8-oxoG not only is a pro-mutagenic genomic base lesion, but also functions as an epigenetic mark and that consequently OGG1 acquire distinct roles in modulation of gene expression. In support, lack of functional OGG1 in Ogg1-/- mice led to an altered expression of genes including those responsible for the aberrant innate and adaptive immune responses and susceptibility to metabolic disorders. Therefore, the present study examined stimulus-driven OGG1-DNA interactions at whole genome level using chromatin immunoprecipitation (ChIP)-coupled sequencing, and the roles of OGG1 enriched on the genome were validated by molecular and system-level approaches. Results showed that signaling levels of cellular ROS generated by TNFα, induced enrichment of OGG1 at specific sites of chromatinized DNA, primarily in the regulatory regions of genes. OGG1-ChIP-ed genes are associated with important cellular and biological processes and OGG1 enrichment was limited to a time scale required for immediate cellular responses. Prevention of OGG1-DNA interactions by siRNA depletion led to modulation of NF-κB's DNA occupancy and differential expression of genes. Taken together these data show TNFα-ROS-driven enrichment of OGG1 at gene regulatory regions in the chromatinized DNA, which is a prerequisite to modulation of gene expression for prompt cellular responses to oxidant stress.
Graphical abstract
The repair protein 8-oxoguanine DNA glycosylase 1 (OGG1) modulates gene expression upon its stimulus-driven binding to gene regulatory regions. ROS generated by receptor ligand interactions, metabolic processes, or environmental exposures produces 8-oxoguanine (8-oxoG) primarily in guanine-rich gene regulatory regions and inactivates OGG1's enzymatic activity by oxidizing it at cysteine residue(s) (OGG1-SOH). OGG1-SOH flips 8-oxoG out of the DNA double helix and induces alterations in adjacent DNA sequences, by which it facilitates binding of transcription factors. This leads to expression of genes and downstream cellular biological responses. Upon the cellular redox is reestablished, genomic 8-oxoG is repaired via the BER pathway. OGG1-SH, enzymatically active OGG1; OGG1-SOH, enzyatically inactive OGG1; BER, base excision repair; red star: 8-oxoguanine; red bar: gene regulatory region; blue bars: exons.
