Cracking the control of RNA polymerase II elongation by 7SK snRNP and P-TEFb

Alexandre J C Quaresma, Andrii Bugai, Matjaz Barboric, Alexandre J C Quaresma, Andrii Bugai, Matjaz Barboric

Abstract

Release of RNA polymerase II (Pol II) from promoter-proximal pausing has emerged as a critical step regulating gene expression in multicellular organisms. The transition of Pol II into productive elongation requires the kinase activity of positive transcription elongation factor b (P-TEFb), which is itself under a stringent control by the inhibitory 7SK small nuclear ribonucleoprotein (7SK snRNP) complex. Here, we provide an overview on stimulating Pol II pause release by P-TEFb and on sequestering P-TEFb into 7SK snRNP. Furthermore, we highlight mechanisms that govern anchoring of 7SK snRNP to chromatin as well as means that release P-TEFb from the inhibitory complex, and propose a unifying model of P-TEFb activation on chromatin. Collectively, these studies shine a spotlight on the central role of RNA binding proteins (RBPs) in directing the inhibition and activation of P-TEFb, providing a compelling paradigm for controlling Pol II transcription with a non-coding RNA.

© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Figures

Figure 1.
Figure 1.
P-TEFb kinase stimulates the transition of Pol II from promoter-proximal pausing into productive elongation. Top: recruitment of Pol II by general transcription factors (GTFs) through TATA-binding protein of the core promoter recognition complex TFIID results in the formation of a PIC. The CTD of Pol II is represented as a tail, wherein white circles depict unphosphorylated Serine residues at position 2, 5 and 7 within the consensus heptapeptide repeat. Black arrow depicts transcription start site (TSS). While rapid Pol II initiation ensues (depicted in light blue), Pol II pauses (depicted in blue) at promoter-proximal pause sites due to the actions of NELF and DSIF which are both in non-phosphorylated forms (white circles). At this stage, the CTD has been phosphorylated already by Cdk7 of TFIIH at Ser5 and Ser7 (yellow circles). A short RNA transcript is depicted in red. Bottom: catalytically active P-TEFb within SEC stimulates the release of paused Pol II into elongation (dashed red arrow) by phosphorylating the CTD at Ser2, NELF and DSIF (green circles). While phosphorylated NELF dissociates from Pol II, phosphorylated DSIF becomes a positive elongation factor and recruits Tat-SF1 and PAF1C to elongating Pol II. In turn, PAF1C can promote the recruitment of Cdk12/CycK, which in concert with P-TEFb catalyzes P-Ser2 during Pol II elongation, yielding an increasingly longer RNA transcript (red).
Figure 2.
Figure 2.
Biogenesis of core and canonical 7SK snRNP. Following the transcription of RN7SK by Pol III, nascent 7SK folds into a structure that may consist of four stem loops (SL1-4) as displayed on the left. LA and MePCE prevent 7SK nucleolytic degradation by binding its 3′-terminal U-rich sequence and by binding the basal part of the 7SK SL1 and capping the 5′ end of 7SK, respectively (Step 1). The capping (depicted as black circle) might provoke the replacement of LA in the transient 7SK snRNP by LARP7, which in addition to the 3′-terminal U-rich sequence binds 7SK SL4, ensuring 7SK stability. Moreover, LARP7 binds MePCE, provoking tighter LARP7-7SK interaction and inhibition of the MePCE capping activity, yielding a stable core 7SK snRNP (Step 2). Finally, HEXIM1/2 dimers bind the proximal and distal parts of 7SK SL1 through their ARMs, leading to the exposure of the dimeric coiled-coil binding surface for active P-TEFb (Cdk9 is in green) phosphorylated at Threonine 186 (depicted as green circle on Cdk9). Inhibition of P-TEFb (Cdk9 is in red) by HEXIM1/2 ensues, concluding formation of the canonical 7SK snRNP (Step 3).
Figure 3.
Figure 3.
Summary of post-translational modifications and proteolysis of 7SK snRNP components that provoke the release of P-TEFb. The model represents the canonical 7SK snRNP complex, in which 7SK, LARP7 and MePCE form core 7SK snRNP that enables binding and inhibition of P-TEFb (Cdk9 is in red) by HEXIM1/2. The arrows depict stimulus-dependent PTMs of HEXIM1, CycT1 and Cdk9, which lead to the release of P-TEFb by disabling key steps that promote the assembly of P-TEFb into 7SK snRNP. Whereas the PTMs in HEXIM1, CycT1 and Cdk9 leave core 7SK snRNP intact, demethylation of 7SK and proteolysis of MePCE destabilize the core, yielding irreversible P-TEFb activation.
Figure 4.
Figure 4.
Brd4 and the dual enzymatic activities of JMJD6 target 7SK snRNP at anti-pause enhancers to trigger Pol II pause release. A-PEs (green) contain either tetra-acetylated histone H4 (Lys5, 8, 12 and 16) or di-acetylated histone H3 (Lys9 and Lys14) (H4/H3Ac), as well as symmetric di-methylated histone H4 (Arg3) (H4R3me2(s)). While the H4/H3Ac mark recruits JMJD6 via Brd4, the H4R3me2(s) mark is bound directly by the 7SK SL1 to tether 7SK snRNP harboring inactive P-TEFb (Cdk9 is in red). The A-PEs loop to target gene promoters through Mediator (not shown) and stimulate Pol II pause release via a series of events. Through its histone demethylase activity targeting H4R3me2(s) and RNA demethylase activity targeting the 5′ 7SK methyl-group in its cap structure (Step 1), JMJD6 ablates the anchoring of 7SK snRNP at A-PEs and destabilizes 7SK, respectively. These actions disintegrate 7SK snRNP and release active P-TEFb (Cdk9 is in green), which is captured cooperatively by Brd4 and JMJD6 at target gene promoters containing the active H4/H3Ac chromatin mark (Step 2). Finally, P-TEFb phosphorylates its three main targets in paused Pol II complex (Step 3), stimulating Pol II elongation.
Figure 5.
Figure 5.
A model of P-TEFb activation on chromatin by 7SK snRNP chromatin adaptor and P-TEFb release factors. The model depicts the P-TEFb activation and de-activation cycle at gene promoter. Specific 7SK snRNP chromatin adaptor factors (Ch-AFs), i.e. a regulatory protein or a chromatin mark, direct the anchoring of a fraction of nucleoplasmic 7SK snRNP to chromatin, harboring inactive P-TEFb (Cdk9 is in red) (Step 1). Upon diverse circumstances, such as cell signaling or emergent nascent transcript, P-TEFb release factors (P-REFs) converge on 7SK snRNP to trigger the liberation of active P-TEFb (Cdk9 is in green) (Step 2). Subsequently, P-TEFb is assembled into SEC and could in concert with the dedicated transcription factor or P-REF promote the release of Pol II from pausing (Step 3). Finally, upon the cessation of the signal stimulating gene transcription, P-TEFb is re-sequestered into 7SK snRNP anchored at promoter (Step 4). Chromatin is represented as a black circle. For clarity, Pol II is omitted from the model. Each of the steps could be subject to control, and for simplicity, possible regulatory mechanisms are not depicted.

References

    1. Strobl L.J., Eick D. Hold back of RNA polymerase II at the transcription start site mediates down-regulation of c-myc in vivo. EMBO J. 1992;11:3307–3314.
    1. Krumm A., Meulia T., Brunvand M., Groudine M. The block to transcriptional elongation within the human c-myc gene is determined in the promoter-proximal region. Genes Dev. 1992;6:2201–2213.
    1. Rougvie A.E., Lis J.T. The RNA polymerase II molecule at the 5′ end of the uninduced hsp70 gene of D. melanogaster is transcriptionally engaged. Cell. 1988;54:795–804.
    1. Kao S.-Y., Calman A.F., Luciw P.A., Peterlin B.M. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature. 1987;330:489–493.
    1. Guo J., Price D.H. RNA Polymerase II Transcription Elongation Control. Chem. Rev. 2013;113:8583–8603.
    1. Jonkers I., Lis J.T. Getting up to speed with transcription elongation by RNA polymerase II. Nat. Rev. Mol. Cell Biol. 2015;16:167–177.
    1. Adelman K., Lis J.T. Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat. Rev. Genet. 2012;13:720–731.
    1. Price D.H. P-TEFb, a cyclin-dependent kinase controlling elongation by RNA polymerase II. Mol. Cell. Biol. 2000;20:2629–2634.
    1. Zhou Q., Li T., Price D.H. RNA polymerase II elongation control. Annu. Rev. Biochem. 2012;81:119–143.
    1. Marshall N.F., Price D.H. Purification of P-TEFb, a transcription factor required for the transition into productive elongation. J. Biol. Chem. 1995;270:12335–12338.
    1. Mancebo H.S., Lee G., Flygare J., Tomassini J., Luu P., Zhu Y., Peng J., Blau C., Hazuda D., Price D., et al. P-TEFb kinase is required for HIV Tat transcriptional activation in vivo and in vitro. Genes Dev. 1997;11:2633–2644.
    1. Wei P., Garber M.E., Fang S.M., Fischer W.H., Jones K.A. A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA. Cell. 1998;92:451–462.
    1. Lu H., Li Z., Xue Y., Zhou Q. Viral-host interactions that control HIV-1 transcriptional elongation. Chem. Rev. 2013;113:8567–8582.
    1. Wada T., Takagi T., Yamaguchi Y., Ferdous A., Imai T., Hirose S., Sugimoto S., Yano K., Hartzog G.A., Winston F., et al. DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs. Genes Dev. 1998;12:343–356.
    1. Yamaguchi Y., Takagi T., Wada T., Yano K., Furuya A., Sugimoto S., Hasegawa J., Handa H. NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation. Cell. 1999;97:41–51.
    1. Palangat M., Meier T.I., Keene R.G., Landick R. Transcriptional pausing at +62 of the HIV-1 nascent RNA modulates formation of the TAR RNA structure. Mol. Cell. 1998;1:1033–1042.
    1. Sanso M., Levin R.S., Lipp J.J., Wang V.Y., Greifenberg A.K., Quezada E.M., Ali A., Ghosh A., Larochelle S., Rana T.M., et al. P-TEFb regulation of transcription termination factor Xrn2 revealed by a chemical genetic screen for Cdk9 substrates. Genes Dev. 2016;30:117–131.
    1. Bentley D.L. Coupling mRNA processing with transcription in time and space. Nat. Rev. Genet. 2014;15:163–175.
    1. Lenasi T., Barboric M. P-TEFb stimulates transcription elongation and pre-mRNA splicing through multilateral mechanisms. RNA Biol. 2010;7:145–150.
    1. Schuller R., Forne I., Straub T., Schreieck A., Texier Y., Shah N., Decker T.M., Cramer P., Imhof A., Eick D. Heptad-specific phosphorylation of RNA polymerase II CTD. Mol. Cell. 2016;61:305–314.
    1. Fujinaga K., Irwin D., Huang Y., Taube R., Kurosu T., Peterlin B.M. Dynamics of human immunodeficiency virus transcription: P-TEFb phosphorylates RD and dissociates negative effectors from the transactivation response element. Mol. Cell. Biol. 2004;24:787–795.
    1. Chen Y., Yamaguchi Y., Tsugeno Y., Yamamoto J., Yamada T., Nakamura M., Hisatake K., Handa H. DSIF, the Paf1 complex, and Tat-SF1 have nonredundant, cooperative roles in RNA polymerase II elongation. Genes Dev. 2009;23:2765–2777.
    1. Wada T., Takagi T., Yamaguchi Y., Watanabe D., Handa H. Evidence that P-TEFb alleviates the negative effect of DSIF on RNA polymerase II-dependent transcription in vitro. EMBO J. 1998;17:7395–7403.
    1. Yu M., Yang W., Ni T., Tang Z., Nakadai T., Zhu J., Roeder R.G. RNA polymerase II-associated factor 1 regulates the release and phosphorylation of paused RNA polymerase II. Science. 2015;350:1383–1386.
    1. Davidson L., Muniz L., West S. 3′ end formation of pre-mRNA and phosphorylation of Ser2 on the RNA polymerase II CTD are reciprocally coupled in human cells. Genes Dev. 2014;28:342–356.
    1. Laitem C., Zaborowska J., Isa N.F., Kufs J., Dienstbier M., Murphy S. CDK9 inhibitors define elongation checkpoints at both ends of RNA polymerase II-transcribed genes. Nat. Struct. Mol. Biol. 2015;22:396–403.
    1. Barboric M., Lenasi T., Chen H., Johansen E.B., Guo S., Peterlin B.M. 7SK snRNP/P-TEFb couples transcription elongation with alternative splicing and is essential for vertebrate development. Proc. Natl. Acad. Sci. U.S.A. 2009;106:7798–7803.
    1. Guiguen A., Soutourina J., Dewez M., Tafforeau L., Dieu M., Raes M., Vandenhaute J., Werner M., Hermand D. Recruitment of P-TEFb (Cdk9-Pch1) to chromatin by the cap-methyl transferase Pcm1 in fission yeast. EMBO J. 2007;26:1552–1559.
    1. Ji X., Zhou Y., Pandit S., Huang J., Li H., Lin C.Y., Xiao R., Burge C.B., Fu X.-D. SR proteins collaborate with 7SK and promoter-associated nascent RNA to release paused polymerase. Cell. 2013;153:855–868.
    1. Lenasi T., Peterlin B.M., Barboric M. Cap-binding protein complex links pre-mRNA capping to transcription elongation and alternative splicing through positive transcription elongation factor b (P-TEFb) J. Biol. Chem. 2011;286:22758–22768.
    1. Ni Z., Schwartz B.E., Werner J., Suarez J.R., Lis J.T. Coordination of transcription, RNA processing, and surveillance by P-TEFb kinase on heat shock genes. Mol. Cell. 2004;13:55–65.
    1. Rahl P.B., Lin C.Y., Seila A.C., Flynn R.A., McCuine S., Burge C.B., Sharp P.A., Young R.A. c-Myc regulates transcriptional pause release. Cell. 2010;141:432–445.
    1. Shim E.Y., Walker A.K., Shi Y., Blackwell T.K. CDK-9/cyclin T (P-TEFb) is required in two postinitiation pathways for transcription in the C. elegans embryo. Genes Dev. 2002;16:2135–2146.
    1. Czudnochowski N., Bosken C.A., Geyer M. Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition. Nat. Commun. 2012;3:842.
    1. Liang K., Gao X., Gilmore J.M., Florens L., Washburn M.P., Smith E., Shilatifard A. Characterization of human cyclin-dependent kinase 12 (CDK12) and CDK13 complexes in C-terminal domain phosphorylation, gene transcription, and RNA processing. Mol. Cell. Biol. 2015;35:928–938.
    1. Mayer A., di Iulio J., Maleri S., Eser U., Vierstra J., Reynolds A., Sandstrom R., Stamatoyannopoulos J.A., Churchman L.S. Native elongating transcript sequencing reveals human transcriptional activity at nucleotide resolution. Cell. 2015;161:541–554.
    1. Barboric M., Nissen R.M., Kanazawa S., Jabrane-Ferrat N., Peterlin B.M. NF-kappaB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II. Mol. Cell. 2001;8:327–337.
    1. Gomes N.P., Bjerke G., Llorente B., Szostek S.A., Emerson B.M., Espinosa J.M. Gene-specific requirement for P-TEFb activity and RNA polymerase II phosphorylation within the p53 transcriptional program. Genes Dev. 2006;20:601–612.
    1. Kanazawa S., Okamoto T., Peterlin B.M. Tat competes with CIITA for the binding to P-TEFb and blocks the expression of MHC class II genes in HIV infection. Immunity. 2000;12:61–70.
    1. Hargreaves D.C., Horng T., Medzhitov R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell. 2009;138:129–145.
    1. Yang Z., Yik J.H., Chen R., He N., Jang M.K., Ozato K., Zhou Q. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol. Cell. 2005;19:535–545.
    1. Jang M.K., Mochizuki K., Zhou M., Jeong H.S., Brady J.N., Ozato K. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol. Cell. 2005;19:523–534.
    1. Hossain M.A., Chung C., Pradhan S.K., Johnson T.L. The yeast cap binding complex modulates transcription factor recruitment and establishes proper histone H3K36 trimethylation during active transcription. Mol. Cell. Biol. 2013;33:785–799.
    1. He N., Liu M., Hsu J., Xue Y., Chou S., Burlingame A., Krogan N.J., Alber T., Zhou Q. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol. Cell. 2010;38:428–438.
    1. Lin C., Smith E.R., Takahashi H., Lai K.C., Martin-Brown S., Florens L., Washburn M.P., Conaway J.W., Conaway R.C., Shilatifard A. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol. Cell. 2010;37:429–437.
    1. Mueller D., Garcia-Cuellar M.P., Bach C., Buhl S., Maethner E., Slany R.K. Misguided transcriptional elongation causes mixed lineage leukemia. PLoS Biol. 2009;7:e1000249.
    1. Sobhian B., Laguette N., Yatim A., Nakamura M., Levy Y., Kiernan R., Benkirane M. HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP. Mol. Cell. 2010;38:439–451.
    1. Smith E., Lin C., Shilatifard A. The super elongation complex (SEC) and MLL in development and disease. Genes Dev. 2011;25:661–672.
    1. Lu H., Li Z., Xue Y., Schulze-Gahmen U., Johnson J.R., Krogan N.J., Alber T., Zhou Q. AFF1 is a ubiquitous P-TEFb partner to enable Tat extraction of P-TEFb from 7SK snRNP and formation of SECs for HIV transactivation. Proc. Natl. Acad. Sci. U.S.A. 2014;111:E15–E24.
    1. Gardini A., Baillat D., Cesaroni M., Hu D., Marinis J.M., Wagner E.J., Lazar M.A., Shilatifard A., Shiekhattar R. Integrator regulates transcriptional initiation and pause release following activation. Mol. Cell. 2014;56:128–139.
    1. Takahashi H., Parmely T.J., Sato S., Tomomori-Sato C., Banks C.A., Kong S.E., Szutorisz H., Swanson S.K., Martin-Brown S., Washburn M.P., et al. Human mediator subunit MED26 functions as a docking site for transcription elongation factors. Cell. 2011;146:92–104.
    1. Dawson M.A., Prinjha R.K., Dittmann A., Giotopoulos G., Bantscheff M., Chan W.I., Robson S.C., Chung C.W., Hopf C., Savitski M.M., et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011;478:529–533.
    1. He N., Chan C.K., Sobhian B., Chou S., Xue Y., Liu M., Alber T., Benkirane M., Zhou Q. Human Polymerase-Associated Factor Complex (PAFc) connects the Super Elongation Complex (SEC) to RNA polymerase II on chromatin. Proc. Natl. Acad. Sci. U.S.A. 2011;108:E636–E645.
    1. Perumal K., Sinha K., Henning D., Reddy R. Purification, characterization, and cloning of the cDNA of human signal recognition particle RNA 3′-adenylating enzyme. J. Biol. Chem. 2001;276:21791–21796.
    1. Sinha K.M., Gu J., Chen Y., Reddy R. Adenylation of small RNAs in human cells. Development of a cell-free system for accurate adenylation on the 3′-end of human signal recognition particle RNA. J. Biol. Chem. 1998;273:6853–6859.
    1. Nguyen V.T., Kiss T., Michels A.A., Bensaude O. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature. 2001;414:322–325.
    1. Yang Z., Zhu Q., Luo K., Zhou Q. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature. 2001;414:317–322.
    1. Barboric M., Yik J.H., Czudnochowski N., Yang Z., Chen R., Contreras X., Geyer M., Matija Peterlin B., Zhou Q. Tat competes with HEXIM1 to increase the active pool of P-TEFb for HIV-1 transcription. Nucleic Acids Res. 2007;35:2003–2012.
    1. Kim Y.K., Mbonye U., Hokello J., Karn J. T-cell receptor signaling enhances transcriptional elongation from latent HIV proviruses by activating P-TEFb through an ERK-dependent pathway. J. Mol. Biol. 2011;410:896–916.
    1. He N., Jahchan N.S., Hong E., Li Q., Bayfield M.A., Maraia R.J., Luo K., Zhou Q. A La-related protein modulates 7SK snRNP integrity to suppress P-TEFb-dependent transcriptional elongation and tumorigenesis. Mol. Cell. 2008;29:588–599.
    1. Jeronimo C., Forget D., Bouchard A., Li Q., Chua G., Poitras C., Therien C., Bergeron D., Bourassa S., Greenblatt J., et al. Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Mol. Cell. 2007;27:262–274.
    1. Michels A.A., Fraldi A., Li Q., Adamson T.E., Bonnet F., Nguyen V.T., Sedore S.C., Price J.P., Price D.H., Lania L., et al. Binding of the 7SK snRNA turns the HEXIM1 protein into a P-TEFb (CDK9/cyclin T) inhibitor. EMBO J. 2004;23:2608–2619.
    1. Yik J.H., Chen R., Nishimura R., Jennings J.L., Link A.J., Zhou Q. Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA. Mol. Cell. 2003;12:971–982.
    1. Krueger B.J., Varzavand K., Cooper J.J., Price D.H. The mechanism of release of P-TEFb and HEXIM1 from the 7SK snRNP by viral and cellular activators includes a conformational change in 7SK. PLoS One. 2010;5:e12335.
    1. Marz M., Donath A., Verstraete N., Nguyen V.T., Stadler P.F., Bensaude O. Evolution of 7SK RNA and its protein partners in metazoa. Mol. Biol. Evol. 2009;26:2821–2830.
    1. Wassarman D.A., Steitz J.A. Structural analyses of the 7SK ribonucleoprotein (RNP), the most abundant human small RNP of unknown function. Mol. Cell. Biol. 1991;11:3432–3445.
    1. Xue Y., Yang Z., Chen R., Zhou Q. A capping-independent function of MePCE in stabilizing 7SK snRNA and facilitating the assembly of 7SK snRNP. Nucleic Acids Res. 2010;38:360–369.
    1. Krueger B.J., Jeronimo C., Roy B.B., Bouchard A., Barrandon C., Byers S.A., Searcey C.E., Cooper J.J., Bensaude O., Cohen E.A., et al. LARP7 is a stable component of the 7SK snRNP while P-TEFb, HEXIM1 and hnRNP A1 are reversibly associated. Nucleic Acids Res. 2008;36:2219–2229.
    1. Bayfield M.A., Yang R., Maraia R.J. Conserved and divergent features of the structure and function of La and La-related proteins (LARPs) Biochim. Biophys. Acta. 2010;1799:365–378.
    1. Chambers J.C., Kurilla M.G., Keene J.D. Association between the 7 S RNA and the lupus La protein varies among cell types. J. Biol. Chem. 1983;258:11438–11441.
    1. Muniz L., Egloff S., Kiss T. RNA elements directing in vivo assembly of the 7SK/MePCE/Larp7 transcriptional regulatory snRNP. Nucleic Acids Res. 2013;41:4686–4698.
    1. Bhattacharya R., Perumal K., Sinha K., Maraia R., Reddy R. Methylphosphate cap structure in small RNAs reduces the affinity of RNAs to La protein. Gene Expr. 2002;10:243–253.
    1. Uchikawa E., Natchiar K.S., Han X., Proux F., Roblin P., Zhang E., Durand A., Klaholz B.P., Dock-Bregeon A.C. Structural insight into the mechanism of stabilization of the 7SK small nuclear RNA by LARP7. Nucleic Acids Res. 2015;43:3373–3388.
    1. Blazek D., Barboric M., Kohoutek J., Oven I., Peterlin B.M. Oligomerization of HEXIM1 via 7SK snRNA and coiled-coil region directs the inhibition of P-TEFb. Nucleic Acids Res. 2005;33:7000–7010.
    1. Li Q., Price J.P., Byers S.A., Cheng D., Peng J., Price D.H. Analysis of the large inactive P-TEFb complex indicates that it contains one 7SK molecule, a dimer of HEXIM1 or HEXIM2, and two P-TEFb molecules containing Cdk9 phosphorylated at threonine 186. J. Biol. Chem. 2005;280:28819–28826.
    1. Yik J.H., Chen R., Pezda A.C., Zhou Q. Compensatory contributions of HEXIM1 and HEXIM2 in maintaining the balance of active and inactive positive transcription elongation factor b complexes for control of transcription. J. Biol. Chem. 2005;280:16368–16376.
    1. Barboric M., Kohoutek J., Price J.P., Blazek D., Price D.H., Peterlin B.M. Interplay between 7SK snRNA and oppositely charged regions in HEXIM1 direct the inhibition of P-TEFb. EMBO J. 2005;24:4291–4303.
    1. Muniz L., Egloff S., Ughy B., Jády B.E., Kiss T. Controlling cellular P-TEFb Activity by the HIV-1 transcriptional transactivator Tat. PLoS Pathog. 2010;6:e1001152.
    1. Yik J.H., Chen R., Pezda A.C., Samford C.S., Zhou Q. A human immunodeficiency virus type 1 Tat-like arginine-rich RNA-binding domain is essential for HEXIM1 to inhibit RNA polymerase II transcription through 7SK snRNA-mediated inactivation of P-TEFb. Mol. Cell. Biol. 2004;24:5094–5105.
    1. Bigalke J.M., Dames S.A., Blankenfeldt W., Grzesiek S., Geyer M. Structure and Dynamics of a Stabilized Coiled-Coil Domain in the P-TEFb Regulator Hexim1. J. Mol. Biol. 2011;414:639–653.
    1. Dames S.A., Schonichen A., Schulte A., Barboric M., Peterlin B.M., Grzesiek S., Geyer M. Structure of the Cyclin T binding domain of Hexim1 and molecular basis for its recognition of P-TEFb. Proc. Natl. Acad. Sci. U.S.A. 2007;104:14312–14317.
    1. Markert A., Grimm M., Martinez J., Wiesner J., Meyerhans A., Meyuhas O., Sickmann A., Fischer U. The La-related protein LARP7 is a component of the 7SK ribonucleoprotein and affects transcription of cellular and viral polymerase II genes. EMBO Rep. 2008;9:569–575.
    1. Chen R., Yang Z., Zhou Q. Phosphorylated positive transcription elongation factor b (P-TEFb) is tagged for inhibition through association with 7SK snRNA. J. Biol. Chem. 2004;279:4153–4160.
    1. Biglione S., Byers S.A., Price J.P., Nguyen V.T., Bensaude O., Price D.H., Maury W. Inhibition of HIV-1 replication by P-TEFb inhibitors DRB, seliciclib and flavopiridol correlates with release of free P-TEFb from the large, inactive form of the complex. Retrovirology. 2007;4:47.
    1. Das R., Yu J., Zhang Z., Gygi M.P., Krainer A.R., Gygi S.P., Reed R. SR proteins function in coupling RNAP II transcription to pre-mRNA splicing. Mol. Cell. 2007;26:867–881.
    1. D'Orso I., Frankel A.D. RNA-mediated displacement of an inhibitory snRNP complex activates transcription elongation. Nat. Struct. Mol. Biol. 2010;17:815–821.
    1. Barboric M., Lenasi T. Kick-sTARting HIV-1 transcription elongation by 7SK snRNP deporTATion. Nat. Struct. Mol. Biol. 2010;17:928–930.
    1. McNamara R.P., McCann J.L., Gudipaty S.A., D'Orso I. Transcription factors mediate the enzymatic disassembly of promoter-bound 7SK snRNP to locally recruit P-TEFb for transcription elongation. Cell Rep. 2013;5:1256–1268.
    1. Flynn R.A., Do B.T., Rubin A.J., Calo E., Lee B., Kuchelmeister H., Rale M., Chu C., Kool E.T., Wysocka J., et al. 7SK-BAF axis controls pervasive transcription at enhancers. Nat. Struct. Mol. Biol. 2016;23:231–238.
    1. Liu W., Ma Q., Wong K., Li W., Ohgi K., Zhang J., Aggarwal A., Rosenfeld M.G. Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release. Cell. 2013;155:1581–1595.
    1. McNamara R.P., Reeder J.E., McMillan E.A., Bacon C.W., McCann J.L., D'Orso I. KAP1 recruitment of the 7SK snRNP complex to promoters enables transcription elongation by RNA polymerase II. Mol. Cell. 2016;61:39–53.
    1. Iyengar S., Farnham P.J. KAP1 protein: an enigmatic master regulator of the genome. J. Biol. Chem. 2011;286:26267–26276.
    1. Bunch H., Zheng X., Burkholder A., Dillon S.T., Motola S., Birrane G., Ebmeier C.C., Levine S., Fargo D., Hu G., et al. TRIM28 regulates RNA polymerase II promoter proximal pausing and pause release. Nat. Struct. Mol. Biol. 2014;21:876–883.
    1. Cherrier T., Le Douce V., Eilebrecht S., Riclet R., Marban C., Dequiedt F., Goumon Y., Paillart J.-C., Mericskay M., Parlakian A., et al. CTIP2 is a negative regulator of P-TEFb. Proc. Natl. Acad. Sci. U.S.A. 2013;110:12655–12660.
    1. Eilebrecht S., Le Douce V., Riclet R., Targat B., Hallay H., Van Driessche B., Schwartz C., Robette G., Van Lint C., Rohr O., et al. HMGA1 recruits CTIP2-repressed P-TEFb to the HIV-1 and cellular target promoters. Nucleic Acids Res. 2014;42:4962–4971.
    1. Ji X., Lu H., Zhou Q., Luo K. LARP7 suppresses P-TEFb activity to inhibit breast cancer progression and metastasis. Elife. 2014;3:e02907.
    1. Sano M., Abdellatif M., Oh H., Xie M., Bagella L., Giordano A., Michael L.H., DeMayo F.J., Schneider M.D. Activation and function of cyclin T-Cdk9 (positive transcription elongation factor-b) in cardiac muscle-cell hypertrophy. Nat. Med. 2002;8:1310–1317.
    1. Fujinaga K., Barboric M., Li Q., Luo Z., Price D.H., Peterlin B.M. PKC phosphorylates HEXIM1 and regulates P-TEFb activity. Nucleic Acids Res. 2012;40:9160–9170.
    1. Contreras X., Barboric M., Lenasi T., Peterlin B.M. HMBA releases P-TEFb from HEXIM1 and 7SK snRNA via PI3K/Akt and activates HIV transcription. PLoS Pathog. 2007;3:e146.
    1. Kim Y.K., Mbonye U., Hokello J., Karn J. T-cell receptor signaling enhances transcriptional elongation from latent HIV proviruses by activating P-TEFb through an ERK-dependent pathway. J. Mol. Biol. 2011;410:896–916.
    1. Mbonye U.R., Wang B., Gokulrangan G., Chance M.R., Karn J. Phosphorylation of HEXIM1 at Tyr271 and Tyr274 promotes release of P-TEFb from the 7SK snRNP complex and enhances proviral HIV gene expression. Proteomics. 2015;15:2078–2086.
    1. Chen R., Liu M., Li H., Xue Y., Ramey W.N., He N., Ai N., Luo H., Zhu Y., Zhou N., et al. PP2B and PP1α cooperatively disrupt 7SK snRNP to release P-TEFb for transcription in response to Ca(2+) signaling. Genes Dev. 2008;22:1356–1368.
    1. Cho S., Schroeder S., Kaehlcke K., Kwon H.S., Pedal A., Herker E., Schnoelzer M., Ott M. Acetylation of cyclin T1 regulates the equilibrium between active and inactive P-TEFb in cells. EMBO J. 2009;28:1407–1417.
    1. Elagib K.E., Rubinstein J.D., Delehanty L.L., Ngoh V.S., Greer P.A., Li S., Lee J.K., Li Z., Orkin S.H., Mihaylov I.S., et al. Calpain 2 activation of P-TEFb drives megakaryocyte morphogenesis and is disrupted by leukemogenic GATA1 mutation. Dev. Cell. 2013;27:607–620.
    1. Sedore S.C., Byers S.A., Biglione S., Price J.P., Maury W.J., Price D.H. Manipulation of P-TEFb control machinery by HIV: recruitment of P-TEFb from the large form by Tat and binding of HEXIM1 to TAR. Nucleic Acids Res. 2007;35:4347–4358.
    1. Michels A.A., Nguyen V.T., Fraldi A., Labas V., Edwards M., Bonnet F., Lania L., Bensaude O. MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner. Mol. Cell. Biol. 2003;23:4859–4869.
    1. Schulte A., Czudnochowski N., Barboric M., Schonichen A., Blazek D., Peterlin B.M., Geyer M. Identification of a cyclin T-binding domain in Hexim1 and biochemical analysis of its binding competition with HIV-1 Tat. J. Biol. Chem. 2005;280:24968–24977.
    1. Cho W.K., Jang M.K., Huang K., Pise-Masison C.A., Brady J.N. Human T-lymphotropic virus type 1 Tax protein complexes with P-TEFb and competes for Brd4 and 7SK snRNP/HEXIM1 binding. J. Virol. 2010;84:12801–12809.
    1. Zhou M., Lu H., Park H., Wilson-Chiru J., Linton R., Brady J.N. Tax interacts with P-TEFb in a novel manner to stimulate human T-lymphotropic virus type 1 transcription. J. Virol. 2006;80:4781–4791.
    1. Ammosova T., Jerebtsova M., Beullens M., Lesage B., Jackson A., Kashanchi F., Southerland W., Gordeuk V.R., Bollen M., Nekhai S. Nuclear targeting of protein phosphatase-1 by HIV-1 Tat protein. J. Biol. Chem. 2005;280:36364–36371.
    1. Ammosova T., Obukhov Y., Kotelkin A., Breuer D., Beullens M., Gordeuk V.R., Bollen M., Nekhai S. Protein phosphatase-1 activates CDK9 by dephosphorylating Ser175. PLoS One. 2011;6:e18985.
    1. Ammosova T., Yedavalli V.R., Niu X., Jerebtsova M., Van Eynde A., Beullens M., Bollen M., Jeang K.T., Nekhai S. Expression of a protein phosphatase 1 inhibitor, cdNIPP1, increases CDK9 threonine 186 phosphorylation and inhibits HIV-1 transcription. J. Biol. Chem. 2011;286:3798–3804.
    1. Barrandon C., Bonnet F., Nguyen V.T., Labas V., Bensaude O. The transcription-dependent dissociation of P-TEFb-HEXIM1-7SK RNA relies upon formation of hnRNP-7SK RNA complexes. Mol. Cell. Biol. 2007;27:6996–7006.
    1. Van Herreweghe E., Egloff S., Goiffon I., Jády B.E., Froment C., Monsarrat B., Kiss T. Dynamic remodelling of human 7SK snRNP controls the nuclear level of active P-TEFb. EMBO J. 2007;26:3570–3580.
    1. Calo E., Flynn R.A., Martin L., Spitale R.C., Chang H.Y., Wysocka J. RNA helicase DDX21 coordinates transcription and ribosomal RNA processing. Nature. 2015;518:249–253.
    1. Bisgrove D.A., Mahmoudi T., Henklein P., Verdin E. Conserved P-TEFb-interacting domain of BRD4 inhibits HIV transcription. Proc. Natl. Acad. Sci. U.S.A. 2007;104:13690–13695.
    1. Itzen F., Greifenberg A.K., Bosken C.A., Geyer M. Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation. Nucleic Acids Res. 2014;42:7577–7590.
    1. Gudipaty S.A., McNamara R.P., Morton E.L., D'Orso I. PPM1G binds 7SK RNA and hexim1 To Block P-TEFb assembly into the 7SK snRNP and sustain transcription elongation. Mol. Cell. Biol. 2015;35:3810–3828.
    1. Castelo-Branco G., Amaral P.P., Engström P.G., Robson S.C., Marques S.C., Bertone P., Kouzarides T. The non-coding snRNA 7SK controls transcriptional termination, poising, and bidirectionality in embryonic stem cells. Genome Biol. 2013;14:1–18.
    1. Meng F.L., Du Z., Federation A., Hu J., Wang Q., Kieffer-Kwon K.R., Meyers R.M., Amor C., Wasserman C.R., Neuberg D., et al. Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell. 2014;159:1538–1548.
    1. Filippakopoulos P., Qi J., Picaud S., Shen Y., Smith W.B., Fedorov O., Morse E.M., Keates T., Hickman T.T., Felletar I., et al. Selective inhibition of BET bromodomains. Nature. 2010;468:1067–1073.
    1. Hainer S.J., Gu W., Carone B.R., Landry B.D., Rando O.J., Mello C.C., Fazzio T.G. Suppression of pervasive noncoding transcription in embryonic stem cells by esBAF. Genes Dev. 2015;29:362–378.
    1. Tan J.L., Fogley R.D., Flynn R.A., Ablain J., Yang S., Saint-André V., Fan Z.P., Do B.T., Laga A.C., Fujinaga K., et al. Stress from nucleotide depletion activates the transcriptional regulator HEXIM1 to suppress melanoma. Mol. Cell. 62:34–46.
    1. Bai X., Kim J., Yang Z., Jurynec M.J., Akie T.E., Lee J., LeBlanc J., Sessa A., Jiang H., DiBiase A., et al. TIF1γ controls erythroid cell fate by regulating transcription elongation. Cell. 2010;142:133–143.

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