The U6 snRNA m6A Methyltransferase METTL16 Regulates MAT2A Intron Retention Through Co-Transcriptional Splicing

Simple item page
dc.contributor.advisorCorey, David R.en
dc.contributor.committeeMemberConrad, Nicholasen
dc.contributor.committeeMemberMendell, Joshua T.en
dc.contributor.committeeMemberTu, Benjaminen
dc.creatorPendleton, Kathryn Elizabethen
dc.date.accessioned2019-09-03T19:55:56Z
dc.date.available2019-09-03T19:55:56Z
dc.date.created2017-08
dc.date.issued2017-07-19
dc.date.submittedAugust 2017
dc.date.updated2019-09-03T19:55:57Z
dc.description.abstractMaintenance of proper levels of the methyl donor S-adenosylmethionine (SAM) is critical for a wide variety of biological processes. We demonstrate that the N6-adenosine methyltransferase METTL16 regulates expression of human MAT2A, which encodes the SAM synthetase expressed in most cells. Upon SAM depletion by methionine starvation, cells induce MAT2A expression by enhanced splicing of a retained intron. Unlike previously studied intron retention events, we show that splicing induction of the MAT2A retained intron is regulated at the level of co-transcriptional splicing. This induction requires METTL16 and its methylation substrate, a vertebrate conserved hairpin (hp1) in the MAT2A 3´ UTR. Increasing METTL16 occupancy on the MAT2A 3´ UTR is sufficient to induce efficient splicing. We propose that under SAM-limiting conditions, METTL16 occupancy on hp1 increases due to inefficient enzymatic turnover, which promotes MAT2A splicing. We further show that METTL16 is the long-unknown methyltransferase for the U6 spliceosomal snRNA. These observations suggest that the conserved U6 snRNA methyltransferase evolved an additional function in vertebrates to regulate SAM homeostasis.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1117308811
dc.identifier.urihttps://hdl.handle.net/2152.5/7194
dc.language.isoenen
dc.subjectIntronsen
dc.subjectMethionine Adenosyltransferaseen
dc.subjectMethyltransferasesen
dc.subjectRNA Splicingen
dc.subjectS-Adenosylmethionineen
dc.titleThe U6 snRNA m6A Methyltransferase METTL16 Regulates MAT2A Intron Retention Through Co-Transcriptional Splicingen
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

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
PENDLETON-DISSERTATION-2017.pdf
Size:
4.98 MB
Format:
Adobe Portable Document Format
Download

License bundle

Now showing 1 - 1 of 1
No Thumbnail Available
Name:
LICENSE.txt
Size:
1.85 KB
Format:
Plain Text
Description:
Download

Collections

UT Southwestern Graduate School of Biomedical Sciences