Abstract
Reversible post-transcriptional modifications on messenger RNA emerge as prevalent phenomena in RNA metabolism. The most abundant among them is N6-methyladenosine (m6A) which is pivotal for RNA metabolism and function; its role in stress response remains elusive. We have discovered that in response to oxidative stress, transcripts are additionally m6A modified in their 5' vicinity. Distinct from that of the translationally active mRNAs, this methylation pattern provides a selective mechanism for triaging mRNAs from the translatable pool to stress-induced stress granules. These stress-induced newly methylated sites are selectively recognized by the YTH domain family 3 (YTHDF3) "reader" protein, thereby revealing a new role for YTHDF3 in shaping the selectivity of stress response. Our findings describe a previously unappreciated function for RNA m6A modification in oxidative-stress response and expand the breadth of physiological roles of m6A.
Highlights
Adequate reprogramming of metabolic activities by environmental stress or suboptimal growth conditions is crucial for cell survival
Stalled mRNAs are deposited in stress granules (SGs); membraneless RNA-protein particles (RNPs) that along with non-translating mRNAs associated with translation initiation complexes contain RNA-binding proteins and proteins with low complexity or intrinsically disordered regions (IDRs) (Buchan & Parker, 2009; Kedersha et al, 2013; Jain et al, 2016; Protter & Parker, 2016)
Two mRNAs were significantly up-regulated under oxidative stress: immediate early response protein 2 (IER2) and FOS transcription factor, which are usually up-regulated by environmental cues that increase intracellular levels of reactive oxygen species (Cekaite et al, 2007)
Summary
Adequate reprogramming of metabolic activities by environmental stress or suboptimal growth conditions is crucial for cell survival. Quantification of the RNA constituents of the SG cores by RNA-sequencing (RNA-Seq) revealed that the targeting efficiency for different mRNAs largely varies and a relatively small fraction of bulk mRNAs accumulates in them (Khong et al, 2017). Through such systemic approaches our knowledge of protein and mRNA components of the SG cores is steadily increasing (Jain et al, 2016; Khong et al, 2017), whether the composition of the shell differs from that of the core remains elusive
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