SAM homeostasis is regulated by CFIm-mediated splicing of MAT2A

eLife

Benjamin P Tu¹  Kuanqing Liu¹  Anna M Scarborough²  Nicholas K Conrad²  Juliana N Flaherty²  Olga V Hunter²  Ashwani Kumar³  Chao Xing⁴ 

[1] Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States;Department of Microbiology, UT Southwestern Medical Center, Dallas, United States;Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, United States;Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, United States;Department of Bioinformatics, UT Southwestern Medical Center, Dallas, United States;Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, United States;

关键词: sam homeostasis;    intron retention;    alternative splicing;    METTL16;    nudt21 cfim25;    MAT2A;    Human;   

DOI  :  10.7554/eLife.64930

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY