On the epigenetic role of guanosine oxidation

Abstract

Chemical modifications of DNA and RNA regulate genome functions or trigger mutagenesis resulting in aging or cancer. Oxidations of macromolecules, including DNA, are common reactions in biological systems and often part of regulatory circuits rather than accidental events. DNA alterations are particularly relevant since the unique role of nuclear and mitochondrial genome is coding enduring and inheritable information. Therefore, an alteration in DNA may represent a relevant problem given its transmission to daughter cells. At the same time, the regulation of gene expression allows cells to continuously adapt to the environmental changes that occur throughout the life of the organism to ultimately maintain cellular homeostasis. Here we review the multiple ways that lead to DNA oxidation and the regulation of mechanisms activated by cells to repair this damage. Moreover, we present the recent evidence suggesting that DNA damage caused by physiological metabolism acts as epigenetic signal for regulation of gene expression. In particular, the predisposition of guanine to oxidation might reflect an adaptation to improve the genome plasticity to redox changes.

Keywords: Guanosine oxidation; Histone modifications; Oxidative stress; Transcription.

Fig. 1

Schematic overview of 8-oxo-dG generation. Cellular 2′-deoxyguanosine undergoes an oxidative process which is mediated by a plethora of different agents. The most abundant intermediate in this process is hydrogen peroxide (H₂O₂) which derives from cellular metabolism and superoxide dismutases (SODs) activity. H₂O₂ promotes ^•OH release in the presence of transition metals. However, other reactive oxygen species (ONOO⁻, ^•OOH, CO₃^•− or ¹O₂) may also intervene in this process and increase the rate of 8-oxo-dG formation.

Fig. 2

Base excision repair of oxidative DNA damage. The presence of 8-oxo-dG in double strand DNA may be repaired before replication by the concerted activity of OGG1, APE1 and translesion synthesis machinery. Alternatively, MTH1 (the homolog of E.coli mutY) recognizes the adenine introduced by replication and excises it. Upon base excision, DNA damage is repaired through the action of APE1 and translesion synthesis machinery.

Fig. 3

H₂O₂fluxes leading to dG oxidation. Cytosolic H₂O₂, generated from mitochondria or cytosolic oxidases, may diffuse to the nucleus. On the other hand, H₂O₂ may also be generated in the nucleus by LSD1 or in the nucleoplasm by nuclear oxidases. Upon conversion of H₂O₂ to ^•OH, dG may be oxidized.

Fig. 4

Several factors regulate OGG1 and 8-oxo-dG removal. OGG1 is regulated by a plethora of stimuli influencing both its expression, stability and eventually activity. ROS accumulation, smoke, nutrient deprivation and temperature imbalance inhibit OGG1, whereas high fat diet, exercise and several post-translational modifications may enhance its activity.

Fig. 5

Factors affecting OGG1 activity in oxidative damage repair. OGG1 recruitment and repair activity may be strongly inhibited by several factors, mainly related to DNA structure compaction and alteration. On the contrary, relaxed chromatin structure and specific DNA sequences facilitate OGG1 recruitment and activity.

Fig. 6

8-oxo-dG accumulation alters gene expression in multiple ways. 8-oxo-dG-mediated recruitment on chromatin has been suggested to weakly dampen RNA polymerase transcription activity. On the contrary, oxidative damage has been demonstrated to promote gene expression through the induction of G-quadruplex formation, chromatin relaxation and reduced DNA methylation.

Fig. 7

Phenotypical alteration identified in OGG1 defective mice. Even though OGG1 absence has not been associated to enhanced tumor onset, it may significantly impair several aspects of mouse physiology, with the induction of inflammation, lipogenesis, and neuron and neural stem cell alteration. Intriguingly, OGG1 deletion has not been demonstrated to have a functional role in aging promotion.