N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis

RNA modifications are integral to regulation of RNA metabolism. One such abundant mRNA modification is m6A, which impacts various aspects of RNA metabolism including splicing, transport and degradation. Current knowledge about proteins recruited to m6A to carry out these molecular processes is still limited. Here we describe a comprehensive and systematic mass spectrometry-based screening of m6A interactors in various cell types and species. Amongst the main findings, we identified G3BP1 as a protein, which is repelled by m6A and which positively regulates mRNA stability in an m6A regulated manner. Furthermore, we identified FMR1 as a novel, RNA sequence context dependent m6A reader, thus revealing a connection between an mRNA modification and an autism spectrum disorder. Collectively, our data represents a rich resource for the community and sheds further light on the complex interplay between m6A, m6A interactors and mRNA homeostasis. Overall design: Transcriptome wide profiling of G3BP1 and G3BP2 binding sites and mRNA half-live measurement after G3BP1 overexpression or knockdown.

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Edupuganti RR, Geiger S, Lindeboom RGH, Shi H, Hsu PJ, Lu Z, Wang SY, Baltissen MPA, Jansen PWTC, Rossa M, Müller M, Stunnenberg HG, He C, Carell T, Vermeulen M