Quality control of chemically damaged RNA

Abstract

The “central dogma” of molecular biology describes how information contained in DNA is transformed into RNA and finally into proteins. In order for proteins to maintain their functionality in both the parent cell and subsequent generations, it is essential that the information encoded in DNA and RNA remains unaltered. DNA and RNA are constantly exposed to damaging agents, which can modify nucleic acids and change the information they encode. While much is known about how cells respond to damaged DNA, the importance of protecting RNA has only become appreciated over the past decade. Modification of the nucleobase through oxidation and alkylation has long been known to affect its base-pairing properties during DNA replication. Similarly, recent studies have begun to highlight some of the unwanted consequences of chemical damage on mRNA decoding during translation. Oxidation and alkylation of mRNA appear to have drastic effects on the speed and fidelity of protein synthesis. As some mRNAs can persist for days in certain tissues, it is not surprising that it has recently emerged that mRNA-surveillance and RNA-repair pathways have evolved to clear or correct damaged mRNA.

How do cells cope with RNA damage and its consequences?

“…Because of their ability to severely dis-rupt the integrity of biological molecules, organisms evolved multiple pathways to rid cells of ROS (23). These include superoxide dismutase, which catalyzes the dismutation of O 2 . into molecular oxygen and hydrogen peroxide (24), and catalase, which catalyzes the decomposition of hydrogen peroxide to water and molecular oxygen (25).…”

“…1C), 8-oxo-7,8-dihydroadenosine (8-oxoA), 5-hydroxyuridine, 5-hydroxycytidine, and cytosine glycol (16, 21,31). Furthermore, products such as 2,6-diamino-4-hydroxy-5-formamidoguanine and 4,6-diamino-5-formamidoadenine are also formed as intermediates during the process of generating 8-oxoG and 8-oxoA (2,32). Oxidation of other cellular components such as lipid peroxidation is also known to introduce oxidative damage to the nucleobase and generate etheno-adducts 1,N 6 -ethenoadenosine and 3,N 4 -ethenocytidine (33).…”

“…Biomolecules possess unique chemical properties that are essential for their function. Yet, the overabundance of reactive species in both the environment and within living cells constantly threatens these properties (1,2). Unwanted modifications to the chemical structure of nucleic acids, proteins, lipids, or carbohydrates often result in drastic effects on the ability of these molecules to carry out these functions.…”

“…Similarly, lipid peroxidation contributes to the pathogenicity of several diseases (5). Because of the reactivity of the oxygen and nitrogen atoms on the nucleobase, nucleic acids are especially susceptible to certain types of chemical damage from sources such as reactive oxygen species (ROS), 2 UV light (UV), and alkylating agents ( Fig. 1A) (1).…”

“…Unless cells have pathways to recognize and degrade/repair mRNAs, chemical damage to mRNA is highly likely to result in the accumulation of aberrant protein products and/or stall ribosomes. Indeed, emerging evidence strongly suggests that quality control for damaged RNA is vital to cell survival and should not be ignored (2,14). To this end, the accumulation of damaged RNA has been correlated with the development of several neurodegenerative diseases (1,2,15,16).…”