The protective role of m1A during stress-induced granulation

Abstract

Post-transcriptional methylation of N6- and N1-adenine can effect transcriptome turnover and translation. Furthermore, the regulatory function of N6-methyladenine (m6A) during heat shock has been uncovered, including the enhancement of the phase separation potential of RNAs. In response to acute stress, e.g. heat shock, the orderly sequestration of mRNAs in stress granules (SGs) is considered important to protect transcripts from the irreversible aggregation. Until recently, the role of N1-methyladenine (m1A) on mRNAs during acute stress response remains largely unknown. Here we show that the methyltransferase complex TRMT6/61A, which generates the m1A tag, is involved in transcriptome protection during heat shock. Our bioinformatics analysis indicates that occurrence of the m1A motif is increased in mRNAs known to be enriched in SGs. Accordingly, the m1A-generating methyltransferase TRMT6/61A accumulated in SGs and mass spectrometry confirmed enrichment of m1A in the SG RNAs. The insertion of a single methylation motif in the untranslated region of a reporter RNA lead to more efficient recovery of protein synthesis from that transcript after the return to normal temperature. Our results demonstrate far-reaching functional consequences of a minimal RNA modification on N1-adenine during acute proteostasis stress.

RNA‐protein interactions: Central players in coordination of regulatory networks

“…[ 69 ] Indeed, in the complex cellular environment, RNA undergoes a number of modifications such as methylation that can influence RNA structures. [ 70,71 ] Despite the increase in single‐stranded regions in vivo , [ 65,66 ] we found that the correlation between amount of double‐stranded regions and number of protein interactions is still conserved in vivo , which further supports the general validity of the trend (Figure S2).…”

“…We discussed the finding that RNA molecules rich in double stranded regions are highly prone to associate with proteins (Figure 2). [ 6 ] Our observations unveil the existence of “feedback loops” (proteins change RNA structure [ 65,70 ] and RNA induces protein assembly [ 30,61 ] ) that regulate cellular events. [ 56,132 ] In addition to protein‐protein and protein‐RNA interactions, [ 108,133 ] the RNA‐RNA network should be better investigated to achieve a full description of the post‐transcriptional layer of regulation.…”

Granulation of m1A-modified mRNAs protects their functionality through cellular stress

“…Following their previous finding that TRMT6 and TRMT61A are greatly enriched on free mRNA in heat-shocked cell lysates ( Alriquet et al., 2019 ), Alriquet et al. (2020) showed that mRNAs containing the m 1 A motif were significantly enriched in SGs ( Figure 1 ).…”

Response to stress in biological disorders: Implications of stress granule assembly and function

“…Analysing the motif of mRNAs in SGs revealed a significant enrichment of transcripts targeted by TRMT6/61A (considered as an m1A writer) 55,56 . And further, TRMT6/61A knockout impaired granulation in response to heat shock and arsenite stress, which indicates TRMT61A is involved in RNA granulation under stressful conditions 57 (Figure 1).…”