KAP1 Recruitment of the 7SK snRNP Complex to Promoters Enables Transcription Elongation by RNA Polymerase II

• Published in: Molecular cell 2016-01, Vol.61 (1), p.39-53
• Main Authors: McNamara, Ryan P., Reeder, Jonathan E., McMillan, Elizabeth A., Bacon, Curtis W., McCann, Jennifer L., D’Orso, Iván
• Format: Article
• Language: English
• Subjects: Binding Sites; Enzyme Activation; Gene Expression Regulation, Viral; HCT116 Cells; HEK293 Cells; HIV - genetics; HIV - metabolism; Humans; Jurkat Cells; Multiprotein Complexes; Positive Transcriptional Elongation Factor B - metabolism; Promoter Regions, Genetic; Repressor Proteins - genetics; Repressor Proteins - metabolism; Ribonucleoproteins, Small Nuclear - genetics; Ribonucleoproteins, Small Nuclear - metabolism; RNA Interference; RNA Polymerase II - genetics; RNA Polymerase II - metabolism; Time Factors; Transcription Elongation, Genetic; Transfection; Tripartite Motif-Containing Protein 28; Virus Activation
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2015.11.004

The transition from transcription initiation to elongation at promoters of primary response genes (PRGs) in metazoan cells is controlled by inducible transcription factors, which utilize P-TEFb to phosphorylate RNA polymerase II (Pol II) in response to stimuli. Prior to stimulation, a fraction of P-TEFb is recruited to promoter-proximal regions in a catalytically inactive state bound to the 7SK small nuclear ribonucleoprotein (snRNP) complex. However, it remains unclear how and why the 7SK snRNP is assembled at these sites. Here we report that the transcriptional regulator KAP1 continuously tethers the 7SK snRNP to PRG promoters to facilitate P-TEFb recruitment and productive elongation in response to stimulation. Remarkably, besides PRGs, genome-wide studies revealed that KAP1 and 7SK snRNP co-occupy most promoter-proximal regions containing paused Pol II. Collectively, we provide evidence of an unprecedented mechanism controlling 7SK snRNP delivery to promoter-proximal regions to facilitate “on-site” P-TEFb activation and Pol II elongation. [Display omitted] •KAP1 recruits 7SK snRNP to most genes containing promoter-proximal paused Pol II•KAP1 delivers inactive P-TEFb kinase to gene promoters for on-site activation•Inducible pathways rely on KAP1-7SK snRNP for P-TEFb delivery and Pol II elongation•HIV exploits KAP1-7SK snRNP to transcribe its genome in response to stimulation McNamara et al. use a combination of biochemical approaches to identify KAP1 as an interactor of the 7SK snRNP complex. Using genomics, they found that the KAP1-7SK snRNP complex is recruited to most promoter-proximal regions containing paused RNA polymerase II to facilitate “on-site” P-TEFb activation and transcriptional pause release.