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The protective role of m1A during stress-induced granulation
Marion Alriquet1,2 , Giulia Calloni1,2 , Adrı´an Martı´nez-Limo´n1,2 , Riccardo Delli Ponti3,4,5 , Gerd Hanspach6 , Martin Hengesbach6 , Gian G. Tartaglia3,4,5,7,8,* , R. Martin Vabulas1,2,9,*
1Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany
2Institute of Biophysical Chemistry, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany
3Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 08003 Barcelona, Spain
4Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain
5Institucio Catalana de Recerca i Estudis Avanc¸ats (ICREA), 08010 Barcelona, Spain
6Institute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany
7Department of Biology ‘Charles Darwin’, Sapienza University of Rome, 00185 Rome, Italy
8Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy
9Present address: Charite´ – Universita¨tsmedizin Berlin, Institute of Biochemistry, 10117 Berlin, Germany
*Correspondence to:Gian G. Tartaglia , Email:gian.tartaglia@iit.it R. Martin Vabulas , Email:martin.vabulas@charite.de;
J Mol Cell Biol, Volume 12, Issue 11, November 2020, Pages 870-880  https://doi.org/10.1093/jmcb/mjaa023
Keyword: stress response, stress granules, N1-methyladenine

Post-transcriptional methylation of N6-adenine and N1-adenine can affect 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 leads 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.