Transcription Factors Mediate the Enzymatic Disassembly of Promoter-Bound 7SK snRNP to Locally Recruit P-TEFb for Transcription Elongation

• Published in: Cell reports (Cambridge) 2013-12, Vol.5 (5), p.1256-1268
• Main Authors: McNamara, Ryan P., McCann, Jennifer L., Gudipaty, Swapna Aravind, D’Orso, Iván
• Format: Article
• Language: English
• Subjects: HEK293 Cells; HeLa Cells; Human immunodeficiency virus; Humans; NF-kappa B - metabolism; Phosphoprotein Phosphatases - metabolism; Phosphorylation; Positive Transcriptional Elongation Factor B - chemistry; Positive Transcriptional Elongation Factor B - metabolism; Promoter Regions, Genetic; Protein Binding; Protein Phosphatase 2C; Protein Structure, Tertiary; Ribonucleoproteins, Small Nuclear - metabolism; Transcription Elongation, Genetic
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.11.003

The transition from transcription initiation into elongation is controlled by transcription factors, which recruit positive transcription elongation factor b (P-TEFb) to promoters to phosphorylate RNA polymerase II. A fraction of P-TEFb is recruited as part of the inhibitory 7SK small nuclear ribonucleoprotein particle (snRNP), which inactivates the kinase and prevents elongation. However, it is unclear how P-TEFb is captured from the promoter-bound 7SK snRNP to activate elongation. Here, we describe a mechanism by which transcription factors mediate the enzymatic release of P-TEFb from the 7SK snRNP at promoters to trigger activation in a gene-specific manner. We demonstrate that Tat recruits PPM1G/PP2Cγ to locally disassemble P-TEFb from the 7SK snRNP at the HIV promoter via dephosphorylation of the kinase T loop. Similar to Tat, nuclear factor (NF)-κB recruits PPM1G in a stimulus-dependent manner to activate elongation at inflammatory-responsive genes. Recruitment of PPM1G to promoter-assembled 7SK snRNP provides a paradigm for rapid gene activation through transcriptional pause release. [Display omitted] •The 7SK snRNP complex keeps a primed P-TEFb kinase at promoters of inducible genes•PPM1G is a coactivator of viral (HIV Tat) and cellular (NF-κB) transcription factors•Transcription factors recruit PPM1G to the promoter-bound 7SK snRNP•PPM1G dephosphorylates the P-TEFb kinase T loop to disassemble the 7SK snRNP The transition from transcription initiation into elongation is essential for rapid gene activation. In this study, D’Orso and colleagues discovered that viral (HIV Tat) and cellular (NF-κB) transcription factors recruit the PPM1G phosphatase to their target genes to dephosphorylate the T loop of the P-TEFb kinase, thereby releasing P-TEFb from the promoter-bound 7SK snRNP complex to activate the transition into elongation. Their work highlights a mechanism for the inducible and rapid gene activation through transcriptional pause release.