SAM homeostasis is regulated by CFIm-mediated splicing of MAT2A.
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 N6-adenosine methyltransferase METTL16 promotes splicing of the MAT2A detained intron by an unknown mechanism. Using an unbiased CRISPR knock-out screen, we identified CFIm25 (NUDT21) as a regulator of MAT2A intron detention and intracellular SAM levels. CFIm25 is a component of the cleavage factor Im (CFIm) complex that regulates poly(A) site selection, but we show it promotes MAT2A splicing independent of poly(A) site selection. CFIm25-mediated MAT2A splicing induction requires the RS domains of its binding partners, CFIm68 and CFIm59 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 CFIm in splicing and SAM metabolism.
['Scarborough|Anna M|AM|0000-0003-3621-234X', 'Flaherty|Juliana N|JN|0000-0002-9745-6762', 'Hunter|Olga V|OV|', 'Liu|Kuanqing|K|', 'Kumar|Ashwani|A|', 'Xing|Chao|C|0000-0002-1838-0502', 'Tu|Benjamin P|BP|0000-0001-5545-9183', 'Conrad|Nicholas K|NK|0000-0002-8562-0895']
D020413:3' Untranslated Regions D064112:Clustered Regularly Interspaced Short Palindromic Repeats D005786:Gene Expression Regulation D057809:HEK293 Cells D006706:Homeostasis D006801:Humans D007438:Introns D008716:Methionine Adenosyltransferase D012326:RNA Splicing D012436:S-Adenosylmethionine D039221:mRNA Cleavage and Polyadenylation Factors
sam homeostasis MAT2A METTL16 alternative splicing chromosomes gene expression human intron retention nudt21 cfim25