mRNA oxidation and its effect on translational expression

Reactive oxygen species have been implicated both in normal biological functions as well as in the etiology/progress for a number of neurodegenerative disorders and aging. Much research has been focused on the characterization and functional effects derived from the oxidative modification of proteins and DNAs. Although RNA is well recognized as a vulnerable target of free radicals and other reactive oxygen species‐mediated reactions, only a few RNA oxidative reactions and their products have been characterized, nor have the biological consequences of RNA oxidation been elucidated in detail. This study showed that, similar to those found in DNA, RNA oxidation leads to degradation and nucleotides base modification. In addition, the oxidized products and their distribution are dependent on the oxidant and reaction conditions used. Typically, under Fenton reaction conditions, the predominant oxidized bases are 5,6‐dihydroxy‐uridine, 2,6‐diamino‐4‐oxo‐5‐formamidopyrimidine (Fapyguanine), 4,6‐diamino‐5‐formamidopyrimidine (Fapyadenine), 8‐oxo‐guanine, and 8‐oxo‐adenine. In in vitro study, the results revealed that oxidation of mRNA led to the suppression of its translation at the level of both initiation and elongation. Moreover, the oxidized mRNA appeared to bind to polysome comparable to that found with control mRNA while the mature protein generation was completely compromised. As a result, premature polypeptides accumulated as a function of the extent of mRNA oxidation. These results support the notion that oxidation of RNA may stall the ribosomal scanning on the oxidized mRNA chain and lead to the generation of premature polypeptides, thus, disrupting cellular metabolism and homeostasis.