Bacterial Response to Oxidative Stress and RNA Oxidation

Bacteria have to cope with oxidative stress caused by distinct Reactive Oxygen Species (ROS), derived not only from normal aerobic metabolism but also from oxidants present in their environments. The major ROS include superoxide O2−, hydrogen peroxide H2O2 and radical hydroxide HO•. To protect cells under oxidative stress, bacteria induce the expression of several genes, namely the SoxRS, OxyR and PerR regulons. Cells are able to tolerate a certain number of free radicals, but high levels of ROS result in the oxidation of several biomolecules. Strikingly, RNA is particularly susceptible to this common chemical damage. Oxidation of RNA causes the formation of strand breaks, elimination of bases or insertion of mutagenic lesions in the nucleobases. The most common modification is 8-hydroxyguanosine (8-oxo-G), an oxidized form of guanosine. The structure and function of virtually all RNA species (mRNA, rRNA, tRNA, sRNA) can be affected by RNA oxidation, leading to translational defects with harmful consequences for cell survival. However, bacteria have evolved RNA quality control pathways to eliminate oxidized RNA, involving RNA-binding proteins like the members of the MutT/Nudix family and the ribonuclease PNPase. Here we summarize the current knowledge on the bacterial stress response to RNA oxidation, namely we present the different ROS responsible for this chemical damage and describe the main strategies employed by bacteria to fight oxidative stress and control RNA damage.

Oxidative Modifications of RNA and Its Potential Roles in Biosystem

Elevated level of oxidized RNA was detected in vulnerable neurons in Alzheimer patients. Subsequently, several diseases and pathological conditions were reported to be associated with RNA oxidation. In addition to several oxidized derivatives, cross-linking and unique strand breaks are generated by RNA oxidation. With a premise that dysfunctional RNA mediated by oxidation is the pathogenetic molecular mechanism, intensive investigations have revealed the mechanism for translation errors, including premature termination, which gives rise to aberrant polypeptides. To this end, we and others revealed that mRNA oxidation could compromise its translational activity and fidelity. Under certain conditions, oxidized RNA can also induce several signaling pathways, to mediate inflammatory response and induce apoptosis. In this review, we focus on the oxidative modification of RNA and its resulting effect on protein synthesis as well as cell signaling. In addition, we will also discuss the potential roles of enzymatic oxidative modification of RNA in mediating cellular effects.

RNA oxidation in chromatin modification and DNA-damage response following exposure to formaldehyde

Formaldehyde is an environmental and occupational chemical carcinogen implicated in the damage of proteins and nucleic acids. However, whether formaldehyde provokes modifications of RNAs such as 8-oxo-7,8-dihydroguanine (8-oxoG) and the role that these modifications play on conferring long-term adverse health effects remains unexplored. Here, we profile 8-oxoG modifications using RNA-immunoprecipitation and RNA sequencing (8-oxoG RIP-seq) to identify 343 RNA transcripts heavily enriched in oxidations in human bronchial epithelial BEAS-2B cell cultures exposed to 1 ppm formaldehyde for 2 h. RNA oxidation altered expression of many transcripts involved in chromatin modification and p53-mediated DNA-damage responses, two pathways that play key roles in sustaining genome integrity and typically deregulated in tumorigenesis. Given that these observations were identified in normal cells exhibiting minimal cell stress and death phenotypes (for example, lack of nuclear shrinkage, F-actin alterations or increased LDH activity); we hypothesize that oxidative modification of specific RNA transcripts following formaldehyde exposure denotes an early process occurring in carcinogenesis analogous to the oxidative events surfacing at early stages of neurodegenerative diseases. As such, we provide initial investigations of RNA oxidation as a potentially novel mechanism underlying formaldehyde-induced tumorigenesis.

Role of RNA Oxidation in Neurodegenerative Diseases

In the history of nucleic acid research, DNA has always been the main research focus. After the sketch of the human genome was completed in 2000, RNA has been started to gain more attention due to its abundancies in the cell and its essential role in cellular physiology and pathologies. Recent studies have shown that RNAs are susceptible to oxidative damage and oxidized RNA is able to break the RNA strand, and affect the protein synthesis, which can lead to cell degradation and cell death. Studies have shown that RNA oxidation is one of the early events in the formation and development of neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. However, its molecular mechanism, as well as its impact on these diseases, are still unclear. In this article, we review the different types of RNA oxidative damage and the neurodegenerative diseases that are reported to be associated with RNA oxidative damage. In addition, we discuss recent findings on the association between RNA oxidative damage and the development of neurodegenerative diseases, which will have great significance for the development of novel strategies for the prevention and treatment of these diseases.

NAT8L mRNA oxidation is linked to neurodegeneration in multiple sclerosis

RNA oxidation has been implicated in neurodegeneration, but the underlying mechanism for such effects is unclear. Recently, we demonstrated extensive RNA oxidation within the neurons in multiple sclerosis (MS) brain. In this report we identified selectively oxidized mRNAs in neuronal cells that pertained to neuropathological pathways. N-acetyl aspartate transferase 8 like (NAT8L) mRNA is one such transcript, whose translated product enzymatically synthesizes N-acetyl aspartic acid (NAA), a neuronal metabolite important for myelin synthesis. We reasoned that impediment of translation of an oxidized NAT8L mRNA will result in reduction in its cognate protein, thus lowering NAA level. This assertion is directly supported by our studies on a model cellular system, an MS animal model and postmortem human MS brain. Reduced NAA level in the brain hampers myelin integrity making neuronal axons more susceptible to damage, which contributes in MS neurodegeneration. Overall, this work provides a framework for mechanistic understanding of the link between RNA oxidation and neurodegenerative diseases.