How do cells cope with RNA damage and its consequences?

Abstract

Edited by Ronald C. Wek Similar to many other biological molecules, RNA is vulnerable to chemical insults from endogenous and exogenous sources. Noxious agents such as reactive oxygen species or alkylating chemicals have the potential to profoundly affect the chemical properties and hence the function of RNA molecules in the cell. Given the central role of RNA in many fundamental biological processes, including translation and splicing, changes to its chemical composition can have a detrimental impact on cellular fitness, with some evidence suggesting that RNA damage has roles in diseases such as neurodegenerative disorders. We are only just beginning to learn about how cells cope with RNA damage, with recent studies revealing the existence of quality-control processes that are capable of recognizing and degrading or repairing damaged RNA. Here, we begin by reviewing the most abundant types of chemical damage to RNA, including oxidation and alkylation. Focusing on mRNA damage, we then discuss how alterations to this species of RNA affect its function and how cells respond to these challenges to maintain proteostasis. Finally, we briefly discuss how chemical damage to noncoding RNAs such as rRNA, tRNA, small nuclear RNA, and small nucleolar RNA is likely to affect their function.

The emerging role of RNA modifications in the regulation of mRNA stability

“…Therefore, these two recent reports suggest that Nm functions as an mRNA stabilizer. As they are oxidized, RNAs can also be alkylated upon exposure to alkylating agents that are either endogenously produced during normal metabolic processes or exogenously provided in the environment 11 . Bases, riboses, and the phosphate backbone of RNA are all vulnerable to alkylation because they contain oxygen and nitrogen atoms.…”

“…The bases in RNA are vulnerable to various forms of chemical damage, such as those induced by reactive oxygen species (ROS), ultraviolet light, and alkylating agents 11 . In particular, ROS-including superoxide, hydroxyl radicals, and hydrogen peroxide-are produced as byproducts of normal oxygen metabolism (e.g., cellular respiration in the mitochondria) and are also generated by various environmental stresses, such as ultraviolet irradiation and heat shock 67 .…”

“…In particular, ROS-including superoxide, hydroxyl radicals, and hydrogen peroxide-are produced as byproducts of normal oxygen metabolism (e.g., cellular respiration in the mitochondria) and are also generated by various environmental stresses, such as ultraviolet irradiation and heat shock 67 . It should be noted that ROS oxidize RNA bases and generate numerous forms of oxidized RNAs 11,67 . These oxidized bases include 8-oxoG, 8-oxo-7,8-dihydroadenosine, 5-hydroxyuridine, 5-hydroxycytidine, and cytosine glycol (Fig.…”

“…1) 1,3-7 : (i) writer proteins (RNAmodifying enzymes), which transfer a specific chemical group to a target position on an RNA molecule; (ii) RNAbinding proteins (RBPs), which specifically recognize the modified nucleotides (reader proteins); and (iii) eraser proteins, which remove specific chemical groups from the modified nucleotides, converting them back into unmodified nucleotides. In certain cases, endogenous or exogenous chemical damage can also generate RNA modifications without the involvement of writer proteins 11,12 . In addition, some modifications are reversible, while others are irreversible.…”

Effects of Oxidative Stress on Protein Translation: Implications for Cardiovascular Diseases

“…Unlike rRNAs, mRNAs and tRNAs are not protected by interaction with proteins and, therefore, are more susceptible to oxidative damage. The nitrogen and oxygen atoms in mRNA and tRNA nucleobases are mostly exposed triggering oxidative modifications, as opposed to double-stranded DNA, where they are relatively protected [152]. The highly reactive OH• radicals, generated during the oxidative stress reactions cascade, can interact with a wide variety of substrates, including free nucleobases, thus causing numerous modifications to RNA.…”