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A methylation prevents binding of U2AF35 to inhibit RNA splicing.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Mendel Mateusz, Delaney Kamila, Pandey Radha Raman, Chen Kuan-Ming, Wenda Joanna M, Vågbø Cathrine Broberg, Steiner Florian A, Homolka David, Pillai Ramesh S,
Project Cellular determinants of subthalamic nucleus function
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Original article (peer-reviewed)

Journal Cell
Volume (Issue) 184(12)
Page(s) 3125 - 3142
Title of proceedings Cell
DOI 10.1016/j.cell.2021.03.062

Open Access

Type of Open Access Repository (Green Open Access)


The N6-methyladenosine (m6A) RNA modification is used widely to alter the fate of mRNAs. Here we demonstrate that the C. elegans writer METT-10 (the ortholog of mouse METTL16) deposits an m6A mark on the 3' splice site (AG) of the S-adenosylmethionine (SAM) synthetase pre-mRNA, which inhibits its proper splicing and protein production. The mechanism is triggered by a rich diet and acts as an m6A-mediated switch to stop SAM production and regulate its homeostasis. Although the mammalian SAM synthetase pre-mRNA is not regulated via this mechanism, we show that splicing inhibition by 3' splice site m6A is conserved in mammals. The modification functions by physically preventing the essential splicing factor U2AF35 from recognizing the 3' splice site. We propose that use of splice-site m6A is an ancient mechanism for splicing regulation.