Splice site m6A methylation prevents binding of U2AF35 to inhibit RNA splicing
| Autor: | Kamila Delaney, Radha Raman Pandey, Florian A. Steiner, David Homolka, Ramesh S. Pillai, K.M. Chen, Mateusz Mendel, Cathrine Broberg Vågbø, Joanna M. Wenda |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
S-Adenosylmethionine
Adenosine Mice 0302 clinical medicine RNA Small Nuclear RNA Precursors Protein biosynthesis U6 snRNA SAM synthetase Conserved Sequence 0303 health sciences Methylation Cell biology RNA splicing Protein Binding RNA Splicing Biology Article General Biochemistry Genetics and Molecular Biology splicing 03 medical and health sciences Splicing factor RNA modification Animals Humans Amino Acid Sequence RNA Messenger Caenorhabditis elegans METT-10 030304 developmental biology Base Sequence METTL16 m6A Methionine Adenosyltransferase Methyltransferases Splicing Factor U2AF spermatogenesis Introns Diet Mutation 3' splice site U2AF35/65 Nucleic Acid Conformation RNA Splice Sites Transcriptome SAM homeostasis 030217 neurology & neurosurgery Homeostasis HeLa Cells |
| Zdroj: | 3125-3142.e25 Cell |
| Popis: | Summary 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. Graphical abstract Highlights • m6A deposited at 3′ splice site by worm METT-10 inhibits splicing • Methylation blocks 3′ splice site recognition by splicing factor U2AF35 • Methylation and splicing inhibition is a response to change in worm diet • Splicing inhibition by 3′ splice site m6A is conserved in mammals m6A methylation of a 3ʹ splice site blocks its recognition by splicing factors to inhibit pre-mRNA splicing in nematodes and mammals. In worms, this mechanism is used to modulate splicing in response to a change in diet. |
| Databáze: | OpenAIRE |
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