Internal modification of RNAs with N-methyladenosine (mA) is a highly conserved means of gene expression control. While the METTL3/METTL14 heterodimer adds this mark on thousands of transcripts in a single-stranded context, the substrate requirements and physiological roles of the second mA writer METTL16 remain unknown. Here we describe the crystal structure of human METTL16 to reveal a methyltransferase domain furnished with an extra N-terminal module, which together form a deep-cut groove that is essential for RNA binding. When presented with a random pool of RNAs, METTL16 selects for methylation-structured RNAs where the critical adenosine is present in a bulge. Mouse 16-cell embryos lacking Mettl16 display reduced mRNA levels of its methylation target, the SAM synthetase Mat2a. The consequence is massive transcriptome dysregulation in ∼64-cell blastocysts that are unfit for further development. This highlights the role of an mA RNA methyltransferase in facilitating early development via regulation of SAM availability.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162343 | PMC |
| http://dx.doi.org/10.1016/j.molcel.2018.08.004 | DOI Listing |
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