7SK methylation by METTL3 promotes transcriptional activity.

Autor: Perez-Pepe M; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA., Desotell AW; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA., Li H; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA., Li W; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA., Han B; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA., Lin Q; RNA Epitranscriptomics and Proteomics Resource, University at Albany, Albany, NY 12222, USA., Klein DE; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA., Liu Y; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA., Goodarzi H; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA., Alarcón CR; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2023 May 10; Vol. 9 (19), pp. eade7500. Date of Electronic Publication: 2023 May 10.
DOI: 10.1126/sciadv.ade7500
Abstrakt: A fundamental feature of cell signaling is the conversion of extracellular signals into adaptive transcriptional responses. The role of RNA modifications in this process is poorly understood. The small nuclear RNA 7SK prevents transcriptional elongation by sequestering the cyclin dependent kinase 9/cyclin T1 (CDK9/CCNT1) positive transcription elongation factor (P-TEFb) complex. We found that epidermal growth factor signaling induces phosphorylation of the enzyme methyltransferase 3 (METTL3), leading to METTL3-mediated methylation of 7SK. 7SK methylation enhanced its binding to heterogeneous nuclear ribonucleoproteins, causing the release of the HEXIM1 P-TEFb complex subunit1 (HEXIM1)/P-TEFb complex and inducing transcriptional elongation. Our findings establish the mechanism underlying 7SK activation and uncover a previously unknown function for the m 6 A modification in converting growth factor signaling events into a regulatory transcriptional response via an RNA methylation-dependent switch.
Databáze: MEDLINE
Externí odkaz: