title: Release of positive transcription elongation factor b (P-TEFb) from 7SK small nuclear ribonucleoprotein (snRNP) activates hexamethylene bisacetamide-inducible protein (HEXIM1) transcription.
abstract: By phosphorylating negative elongation factors and the C-terminal domain of RNA polymerase II (RNAPII), positive transcription elongation factor b (P-TEFb), which is composed of CycT1 or CycT2 and CDK9, activates eukaryotic transcription elongation. In growing cells, it is found in active and inactive forms. In the former, free P-TEFb is a potent transcriptional coactivator. In the latter, it is inhibited by HEXIM1 or HEXIM2 in the 7SK small nuclear ribonucleoprotein (snRNP), which contains, additionally, 7SK snRNA, methyl phosphate-capping enzyme (MePCE), and La-related protein 7 (LARP7). This P-TEFb equilibrium determines the state of growth and proliferation of the cell. In this study, the release of P-TEFb from the 7SK snRNP led to increased synthesis of HEXIM1 but not HEXIM2 in HeLa cells, and this occurred only from an unannotated, proximal promoter. ChIP with sequencing revealed P-TEFb-sensitive poised RNA polymerase II at this proximal but not the previously annotated distal HEXIM1 promoter. Its immediate upstream sequences were fused to luciferase reporters and were found to be responsive to many P-TEFb-releasing compounds. The superelongation complex subunits AF4/FMR2 family member 4 (AFF4) and elongation factor RNA polymerase II 2 (ELL2) were recruited to this proximal promoter after P-TEFb release and were required for its transcriptional effects. Thus, P-TEFb regulates its own equilibrium in cells, most likely to maintain optimal cellular homeostasis.
authors: From the Departments of Medicine, Microbiology, and Immunology, Rosalind Russell Medical Research Center, University of California, San Francisco, California 94143-0703, and.
authors: Pingyang
authors: P
authors: Liu
authors: Yanhui
authors: Y
authors: Xiang
authors: Koh
authors: K
authors: Fujinaga
authors: Koen
authors: K
authors: Bartholomeeusen
authors: Kyle A
authors: KA
authors: Nilson
authors: David H
authors: DH
authors: Price
authors: B Matija
authors: BM
authors: Peterlin
mesh_terms: D056906:Cyclin T / Q000235:genetics / Q000378:metabolism*; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008780:Methyltransferases / Q000096:biosynthesis / Q000235:genetics; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D012261:Ribonucleoproteins / Q000096:biosynthesis / Q000235:genetics; D017411:Ribonucleoproteins, Small Nuclear / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology*; D035602:Transcriptional Elongation Factors
chemical_list: C471348:AFF4 protein, human; C503684:CCNT1 protein, human; D056906:Cyclin T; C476123:HEXIM1 protein, human; C501428:HEXIM2 protein, human; C528908:Larp7 protein, human; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D012261:Ribonucleoproteins; D017411:Ribonucleoproteins, Small Nuclear; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; C547279:MePCE protein, human; D008780:Methyltransferases; D042925:Positive Transcriptional Elongation Factor B; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9
keywords: Cyclin-dependent Kinase (CDK); Cyclins; Promoters; RNA Polymerase II; Transcription