mRNA Stability Is Regulated By Dynamic m6A RNA Methylation

rna methylation

Messenger RNA (mRNA) is a single-stranded RNA molecule that is essential in mediating the transfer of genetic information from DNA by serving as a template for protein synthesis. There are several mechanisms involved in regulating the stability of messenger RNA to influence the level and timing of protein production.  Such mechanisms include regulatory elements such as sequence elements or structural motifs that can target mRNA for degradation.

Furthermore, post-transcriptional modifications such as dynamic methylation of mRNA could also be involved in the regulatory process. One such post-transcriptional modification is the methylation of adenosine at the N6 position to form N6-methyladenosine (m6A) in mRNA. The recent discovery of m6A demethylases suggests a potentially important role for this modification in the control of mRNA metabolism.  Proteins from the YTH family (YTHDF2 and YTHDF3) have been found to selectively bind m6A in mammals and exert regulatory functions. Researchers at the University of Chicago sought to shed more light on the function of the m6A modification and establish the role of the YTHDF2 protein in RNA regulation.

Using techniques including photoactivatable ribonucleoside crosslinking and immunoprecipitation (PAR-CLIP) and RNA immunoprecipitation sequencing (RIP-seq), the authors show that m6A is selectively recognized by the YTHDF2 “reader” protein to regulate RNA degradation.  This work further contributes to our understanding of the functional significance of the m6A modification in RNA as a way to regulate translational potential via mRNA metabolism.

 Their findings are summarized below:
  • YTHDF2 targets over 3,000 cellular RNAs with a conserved core motif of G(m6A)C, including mRNAs and non-coding RNAs.
  • Binding of YTHDF2 to RNA results in localization from the translatable pool to mRNA decay sites.
  • The YTHDF2 carboxy-terminal domain selectively binds to m6A-containing RNA, whereas the amino-terminal domain localizes the YTHDF2-mRNA complex to cellular RNA decay sites.

 

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Source: Read more about their findings and get all of the details here: Wang et al., N6 –methyladenosine-Dependent Regulation of Messenger RNA Stability. Nature (2013), Nov 27. doi: 10.1038/nature12730.

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