Context-Dependent Roles of RNA Modifications in Stress Responses and Diseases

Abstract

RNA modifications are diverse post-transcriptional modifications that regulate RNA metabolism and gene expression. RNA modifications, and the writers, erasers, and readers that catalyze these modifications, serve as important signaling machineries in cellular stress responses and disease pathogenesis. In response to stress, RNA modifications are mobilized to activate or inhibit the signaling pathways that combat stresses, including oxidative stress, hypoxia, therapeutic stress, metabolic stress, heat shock, DNA damage, and ER stress. The role of RNA modifications in response to these cellular stressors is context- and cell-type-dependent. Due to their pervasive roles in cell biology, RNA modifications have been implicated in the pathogenesis of different diseases, including cancer, neurologic and developmental disorders and diseases, and metabolic diseases. In this review, we aim to summarize the roles of RNA modifications in molecular and cellular stress responses and diseases.

The Identification of Two RNA Modification Patterns and Tumor Microenvironment Infiltration Characterization of Lung Adenocarcinoma

“…A-to-I editing consists of the irreversible conversion of adenosine to inosine catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes (Marceca et al, 2021). These RNA modification patterns participate in various physiological processes and play important regulatory roles in diseases including cancers, neurologic and metabolic diseases (Wilkinson et al, 2021).…”

Epitranscriptomic Reprogramming Is Required to Prevent Stress and Damage from Acetaminophen

“…The protection comes at the levels of tRNA modification and translation, with Alkbh8 catalyzing tRNA modifications and translationally regulating the production of stress response proteins. Wobble U writers in yeast, mice and humans have previously been shown to play key roles in responding to stress by enhancing the translation of ROS detoxification, DNA damage response and metabolic proteins [62][63][64][65]. For example, deficiencies in the mcm 5 U writer tRNA methyltransferase 9 (Trm9) in yeast sensitize cells to DNA damaging agents and disrupt cell cycle transitions, with decreased translation of ribonucleotide reductase genes driving these phenotypes [7,66].…”

Epitranscriptomic reprogramming is required to prevent stress and damage from acetaminophen

“…The protection comes at the levels of tRNA modification and translation, with Alkbh8 catalyzing tRNA modifications and translationally regulating the production of stress response proteins. Wobble U writers in yeast, mice and humans have previously been shown to play key roles in responding to stress by enhancing the translation of key ROS detoxification, DNA damage response and metabolic proteins (Chionh et al 2016; Schaffrath and Leidel 2017; Villahermosa and Fleck 2017; Wilkinson, Cui, and He 2021). For example, deficiencies in the mcm 5 U writer tRNA methyltransferase 9 (Trm9) in yeast sensitize cells to DNA damaging agents and disrupt cell cycle transitions, with decreased translation of ribonucleotide reductase genes driving these phenotypes (Begley et al 2007; Deng et al 2015; Patil et al 2012).…”

“…Adenosine-based modifications m 1 A, and m 6 A were also measured to be dysregulated in the Alkbh8 Def liver tissue compared to WT after daily APAP exposure. All measured modifications within the chronic timeline are shown in (Supplemental Fig.7) and (Supplemental Table1).DiscussionHepatoxic effects of APAP toxicity have been widely reported which include oxidative stress, impaired mitochondrial function, lipid peroxidation, nuclear DNA fragmentation and necrotic cell death(Du, Ramachandran, and Jaeschke 2016;Jaeschke and Ramachandran 2018; responding to stress by enhancing the translation of key ROS detoxification, DNA damage response and metabolic proteins(Chionh et al 2016;Schaffrath and Leidel 2017;Villahermosa and Fleck 2017;Wilkinson, Cui, and He 2021). For example, deficiencies in the mcm 5 U writer tRNA methyltransferase 9 (Trm9) in yeast sensitize cells to DNA damaging agents and disrupt cell cycle transitions, with decreased translation of ribonucleotide reductase genes driving these phenotypes(Begley et al 2007;Deng et al 2015;Patil et al 2012).…”