Wanted and unwanted modifications of mRNA and their effect on gene expression and signaling

RNA plays essential roles in transmitting and decoding genetic information, as well as carrying out enzymatic functions during transcription and translation. The function of the polymer is determined by the unique structures of its four nucleobases, which dictate how the molecule interacts with itself, other RNAs, and proteins. As a result, modifications to the bases often impact RNA function by altering these interactions. While we have known for decades that tRNA, rRNA, and mRNA are modified, recent research has shed more light on the functional importance of these internal modifications in mRNAs. In addition to enzyme-mediated modifications, mRNA is also susceptible to damage-induced alterations. These arise from endogenous and exogenous alkylating, oxidizing, and cross-linking agents, as well as exposure to ultraviolet radiation. Many of these modifications severely disrupt tRNA-mRNA interactions, often leading to ribosome stalling. An integrating theme of this review is that both enzymatic and damage-induced modifications are actively sensed by the cell, with damage-induced modifications in particular engaging dedicated quality control pathways and stress-response programs that regulate gene expression and cellular fate. We begin this review by discussing the most abundant enzymatic mRNA modifications and focus on their impact on translation before turning to damage-induced lesions and the ribosome-based quality control machinery that resolves them. We conclude by discussing the remarkable discovery that damaged mRNA, through its impact on ribosome collisions, activates the integrated stress response and ribotoxic stress response to reprogram gene expression, and, under severe conditions, determine cell fate.