m6A governs length-dependent enrichment of mRNAs in stress granules

ABSTRACT Stress granules are biomolecular condensates composed of protein and mRNA. Long mRNAs are enriched in stress granules, which is thought to reflect the ability of long mRNAs to form multiple RNA-RNA interactions with other mRNAs. RNA-RNA interactions are thus thought to be critical for stress granule formation. Stress granule-enriched mRNAs also often contain multiple N 6 -methyladenosine (m 6 A) residues. YTHDF proteins bind m 6 A, creating mRNA-protein complexes that partition into stress granules. Here we determine the basis of length-dependent enrichment of mRNAs in stress granules. We show that depletion of m 6 A is sufficient to abrogate the length-dependent enrichment of mRNAs in stress granules. We show that the presence of m 6 A predicts which mRNAs are enriched. m 6 A formation is triggered by long exons, which are often found in long mRNAs, accounting for the link between m 6 A, length and stress granule enrichment. Thus, length-dependent enrichment of mRNAs in stress granules is driven by YTHDF-mRNA interactions.