Open AccessSplice site m6A methylation prevents binding of U2AF35 to inhibit RNA splicing
Author(s) -
Mateusz Mendel,
Kamila Delaney,
Radha Raman Pandey,
Kuan-Ming Chen,
Joanna M. Wenda,
Cathrine Broberg Vågbø,
Florian Steiner,
David Homolka,
Ramesh S. Pillai
Publication year - 2021
Publication title -
cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 26.304
H-Index - 776
eISSN - 1097-4172
pISSN - 0092-8674
DOI - 10.1016/j.cell.2021.03.062
Subject(s) - biology , rna splicing , splice , methylation , rna , alternative splicing , binding site , genetics , splice site mutation , rna binding protein , microbiology and biotechnology , computational biology , gene , exon
Summary The N 6 -methyladenosine (m 6 A) 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 m 6 A 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 m 6 A-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 m 6 A 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 m 6 A is an ancient mechanism for splicing regulation.
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