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Methylation of Structured RNA by the m6A Writer METTL16 Is Essential for Mouse Embryonic Development

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Mendel Mateusz, Chen Kuan-Ming, Homolka David, Gos Pascal, Pandey Radha Raman, McCarthy Andrew A., Pillai Ramesh S.,
Project Genome protection by germline small RNAs
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Original article (peer-reviewed)

Journal Molecular Cell
Volume (Issue) 71(6)
Page(s) 986 - 1000.e11
Title of proceedings Molecular Cell
DOI 10.1016/j.molcel.2018.08.004

Open Access

Type of Open Access Publisher (Gold Open Access)


Internal modification of RNAs with N6-methyladenosine (m6A) 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 m6A 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 m6A RNA methyltransferase in facilitating early development via regulation of SAM availability.