M6A governs length-dependent enrichment of mRNAs in stress granules.

Abstract

Stress granules are biomolecular condensates composed of protein and mRNA. One feature of stress granule-enriched mRNAs is that they are often longer than average. Another feature of stress granule-enriched mRNAs is that they often contain multiple N6-methyladenosine (m6A) residues. m6A is bound by the YTHDF proteins, creating mRNA-protein complexes that partition into stress granules in mammalian cells. Here we show that length-dependent enrichment of mRNAs in stress granules is mediated by m6A. Long mRNAs often contain one or more long exons, which are preferential sites of m6A formation. In mammalian cells lacking m6A, long mRNAs no longer show preferential stress granule enrichment. Furthermore, we show that m6A abundance more strongly predicts which short or long mRNAs are enriched in stress granules, rather than length alone. Thus, mRNA length correlates with mRNA enrichment in stress granules owing to the high prevalence of m6A in long mRNAs.