8-Oxoguanine DNA glycosylase 1: Beyond repair of the oxidatively modified base lesions

Abstract

Oxidative stress and the resulting damage to genomic DNA are inevitable consequences of endogenous physiological processes, and they are amplified by cellular responses to environmental exposures. One of the most frequent reactions of reactive oxygen species with DNA is the oxidation of guanine to pre-mutagenic 8-oxo-7,8-dihydroguanine (8-oxoG). Despite the vulnerability of guanine to oxidation, vertebrate genes are primarily embedded in GC-rich genomic regions, and over 72% of the promoters of human genes belong to a class with a high GC content. In the promoter, 8-oxoG may serve as an epigenetic mark, and when complexed with the oxidatively inactivated repair enzyme 8-oxoguanine DNA glycosylase 1, provide a platform for the coordination of the initial steps of DNA repair and the assembly of the transcriptional machinery to launch the prompt and preferential expression of redox-regulated genes. Deviations/variations from this artful coordination may be the etiological links between guanine oxidation and various cellular pathologies and diseases during ageing processes.

Keywords: 8-oxoguanine; DNA methylation; Epigenetic; Gene expression regulation; OGG1.

Graphical abstract

Fig. 1

The repair activity of OGG1 is tightly controlled by protein-protein interactions and post-translational modifications. APE1, apurinic/apyrimidic (AP) endonuclease 1; XRCC1, X-ray repair cross complementing 1; CUX1, Cut homeobox 1; HDAC, histone deacetylase; PARylation, Poly(ADP-ribosyl)ation; PARP1, Poly(ADP-ribose) polymerase 1; OGT, O-GlcNAc transferase. Red, up-regulation; Green, down-regulation; Black, no change.

Fig. 2

Genome-wide distribution of OGG1 in response to stimuli. Flag-OGG1-expressing cells were exposed to TNF-α for 30 min. ChIP-ed DNA was sequenced (GSE #: GSE75652) and the enrichment of OGG1 was analyzed. The diagram illustrates the genome-wide enrichment of OGG1 within 1–10 kb from transcription start sites (TSS).

Fig. 3

Positional value of 8-oxoG for the DNA occupancy of NF-κB. (a) Binding to 8-oxoG 8–11 bp upstream from the motif, OGG1 accelerates NF-κB occupancy . Sequence of the DNA fragment containing a NF-κB motif used in the EMSA assay is derived from the human TNF promoter. 8-oxoG substitution was carried out individually (shown in red). (b) Frequency of G at each base in the surrounding sequences 10-bp up- and downstream from the motifs of 70 functional human κB sites (data provided by Wang et al. [89]). The average frequency of one of four nucleobases at each position is considered as 25%.

Fig. 4

Enzymatically inactive OGG1 binding to promoter-contained 8-oxoG facilitates transcription factor binding and the assembly of the transcriptional machinery. OGG1 binding to its substrate bends DNA and induces allosteric alteration of DNA, that facilitates NF-κB occupancy and the assembly of the transcription machinery.

Fig. 5

Transcriptionally active genes are embedded in a GC-rich fraction of chromatin. Upper panel, actively or constitutively transcribed genes are densely distributed in high GC-content regions. Lower panel, genes sparsely distributed in GC-poor regions are transcribed in a tissue-dependent or developmentally regulated manner.

Fig. 6

Oxidative stress-mediated inactivation of OGG1 enzymatic activity converts the OGG1–DNA complex as part of transcriptional machinery. Under the physiological redox state, OGG1 fulfills its repair function in the DNA BER pathway (left panel). Upon oxidative stress OGG1's enzymatic function is compromised by cysteine modifications, and the OGG1-8-oxoG-DNA complex is utilized by NF-κB-centered transcriptional machinery, leading to the transcription of target genes (middle panel). When redox balance is re-established, OGG1 regains its repair function and, by introducing repair intermediates into the promoter, may disrupt the actions of transcriptional machinery.

Fig. 7

OGG1-DNA complex at 8-oxoG may unlock the transcriptional repression caused by cytosine methylation. (a) MBPs recognize methyl-CpG and recruite co-repressor molecules to silence transcription. (b) Binding to oxidized guanine in the opposite strand, OGG1 may interfere the interaction of MBPs with their substrates, and recruite transcriptional machinery components to activate transcription.