Reading RNA modifications


It has been known for many years that mRNA molecules are decorated with a large number of distinct chemical modifications. In recent years, enzymes, which catalyse and remove these modifications from mRNA molecules have been identified and characterized. The research field called  ‘epitranscriptomics’, which studies the impact of these dynamic mRNA modifications on mRNA homeostasis and regulation of gene expression is currently a very hot topic in biology. One particularly important mRNA modification is N6-methyladenosine (m6A).

Recent work has revealed that m6A plays an important role in regulating various aspects of mRNA homeostasis such as splicing, mRNA degradation and mRNA translation. Various biological phenomena have been associated with m6A such as obesity, fertilization and cancer. One very important question is how m6A affects mRNA homeostasis. Previous work has shown that the YTH domain is a specific m6A ‘reader’ domain, suggesting that YTH domain containing proteins act as effectors of m6A in cells. Whether additional m6A reader proteins exist is currently unclear. Furthermore, it is currently unknown whether certain proteins are specifically repelled by m6A containing mRNA sequences, a phenomenon which is observed, for example, for methylated DNA.

Researchers in the lab of Michiel Vermeulen, together with colleagues in Nijmegen, Munich and Chicago, performed a global mass spectrometry-based interaction screening for m6A readers in various cell types and mRNA sequence contexts. Their data reveals that YTH proteins are conserved and cell-type independent m6A readers. In addition, they identified a number of sequence context dependent m6A readers, including FMR1, thus linking m6A to regulation of mRNA translation and fragile X-linked mental retardation. Strikingly, their data also revealed that many proteins have a clear preference for unmodified versus m6A containing mRNA. One such repelled protein is G3BP1, a known stress granule protein. Subsequent RNA sequencing and proteomics experiments revealed that G3BP1 and FMR1 regulate m6A-linked mRNA stability and translation rates, respectively. In summary, these experiments have revealed an intricate interplay between m6A readers and repelled proteins and various aspects of mRNA homeostasis.

This work was recently published in the prestigious journal Nature Structural and Molecular Biology.



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