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.

This work was funded by the European Research Council grants MetaMeta_311522 (R.M.V.), RIBOMYLOME_309545 (G.G.T.) and ASTRA_855923 (G.G.T). G.G.T. acknowledges support of the H2020 projects IASIS_727658 and INFORE_825080, the Spanish Ministry of Economy and Competitiveness BFU2017-86970-P as well as the collaboration with Peter St. George-Hyslop financed by the Wellcome Trust. R.M.V. acknowledges support by the Deutsche Forschungsgemeinschaft (DFG) grant EXC115. M.H. is funded by DFG CRC902 “Molecular Principles of RNA-based Regulation”