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.