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Splice site m⁶A methylation prevents binding of U2AF35 to inhibit RNA splicing.

ABSTRACT: 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.

SUBMITTER: Mendel M

PROVIDER: S-EPMC8208822 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Splice site m6A methylation prevents binding of U2AF35 to inhibit RNA splicing.

Mendel Mateusz M Delaney Kamila K Pandey Radha Raman RR Chen Kuan-Ming KM Wenda Joanna M JM Vågbø Cathrine Broberg CB Steiner Florian A FA Homolka David D Pillai Ramesh S RS

Cell 20210429 12

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 h ...[more]

PMID: 33930289

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RNA m6A methylation of 3ʹ splice site prevents binding of U2AF35 to inhibit splicing

Project description:OThe N6-methyladenosine (m6A) RNA modification is widely used to alter the fate of mRNAs. Here we demonstrate that the C. elegans writer METT-10 (orthologue of mouse METTL16) deposits an m6A mark on the 3′ splice site (AG) of the 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.

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RNA m6A methylation of 3ʹ splice site prevents binding of U2AF35 to inhibit splicing

Project description:RNA m6A methylation of 3ʹ splice site prevents binding of U2AF35 to inhibit splicing

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Splice site m6A methylation prevents binding of DGCR8 to suppress KRT4 pre-mRNA splicing in oral squamous cell carcinoma.

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