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

ABSTRACT: 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.

ORGANISM(S): Mus musculus Bombyx mori Caenorhabditis elegans

PROVIDER: GSE146873 | GEO | 2021/04/29

REPOSITORIES: GEO

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

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Project description:Recent work has associated point mutations in both zinc fingers (ZnF) of the spliceosome component U2AF35 with malignant transformation. However, surprisingly little is known about the functionality of the U2AF35 ZnF domains in general. Here we have analyzed key functionalities of the ZnF domains of mammalian U2AF35 and its paralog U2AF26. Both ZnFs are required for splicing regulation, whereas only ZnF2 controls protein stability and contributes to the interaction with U2AF65. These features are confirmed in a naturally occurring splice variant of U2AF26 lacking ZnF2, that is strongly induced upon activation of primary mouse T cells and localized in the cytoplasm. Using Ribo-Seq in a model T cell line we provide evidence for a role of U2AF26 in activating cytoplasmic steps in gene expression, notably translation. Consistently, an MS2 tethering assay shows that cytoplasmic U2AF26/35 increase translation when localized to the 5’UTR of a model mRNA. This regulation is partially dependent on ZnF1 thus providing a connection between a core splicing factor, the ZnF domains and the regulation of translation. Altogether, our work reveals unexpected functions of U2AF26/35 and their ZnF domains, thereby contributing to a better understanding of their role and regulation in mammalian cells.

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Expression analysis of mutant U2AF35 transduced cells

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