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

•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

SummaryThe 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.

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