SAM homeostasis is regulated by CFI<sub>m</sub>-mediated splicing of MAT2A.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33949310.
- Also identified by DOI 10.7554/eLife.64930 and PMC identifier 8139829.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
S-adenosylmethionine (SAM) is the methyl donor for nearly all cellular methylation events. Cells regulate intracellular SAM levels through intron detention of MAT2A, the only SAM synthetase expressed in most cells. The N<sup>6</sup>-adenosine methyltransferase METTL16 promotes splicing of the MAT2A detained intron by an unknown mechanism. Using an unbiased CRISPR knock-out screen, we identified CFI<sub>m</sub>25 (NUDT21) as a regulator of MAT2A intron detention and intracellular SAM levels. CFI<sub>m</sub>25 is a component of the cleavage factor Im (CFI<sub>m</sub>) complex that regulates poly(A) site selection, but we show it promotes MAT2A splicing independent of poly(A) site selection. CFI<sub>m</sub>25-mediated MAT2A splicing induction requires the RS domains of its binding partners, CFI<sub>m</sub>68 and CFI<sub>m</sub>59 as well as binding sites in the detained intron and 3´ UTR. These studies uncover mechanisms that regulate MAT2A intron detention and reveal a previously undescribed role for CFI<sub>m</sub> in splicing and SAM metabolism.
Medical subject headings
- Gene Expression Regulation
- Homeostasis
- Methionine Adenosyltransferase
- RNA Splicing
- S-Adenosylmethionine
- mRNA Cleavage and Polyadenylation Factors