SAM Homeostasis Is Regulated by CFIm-Mediated Splicing of MAT2A

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dc.contributor.advisorTu, Benjaminen
dc.contributor.committeeMemberMendell, Joshua T.en
dc.contributor.committeeMemberGreen, Carla B.en
dc.contributor.committeeMemberConrad, Nicholasen
dc.creatorScarborough, Anna Maurineen
dc.creator.orcid0000-0003-3621-234X
dc.date.accessioned2023-09-14T22:28:39Z
dc.date.available2023-09-14T22:28:39Z
dc.date.created2021-08
dc.date.issuedAugust 2021
dc.date.submittedAugust 2021
dc.date.updated2023-09-14T22:28:39Z
dc.description.abstractS-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 3ยด UTR. These studies uncover mechanisms that regulate MAT2A intron detention and reveal a previously undescribed role for CFIm in splicing and SAM metabolism.en
dc.format.mimetypeapplication/pdfen
dc.identifier.urihttps://hdl.handle.net/2152.5/10192
dc.language.isoenen
dc.subjectGene Expression Regulationen
dc.subjectHomeostasisen
dc.subjectMethionine Adenosyltransferaseen
dc.subjectRNA Splicingen
dc.subjectS-Adenosylmethionineen
dc.subjectmRNA Cleavage and Polyadenylation Factorsen
dc.titleSAM Homeostasis Is Regulated by CFIm-Mediated Splicing of MAT2Aen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineBiological Chemistryen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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