Controlling the Elongation Phase of Transcription with P-TEFb

Department of Medicine, Microbiology and Immunology, Rosalind Russell Medical Research Center, University of California, San Francisco, San Francisco, California 94143, USA.
Molecular Cell (Impact Factor: 14.02). 09/2006; 23(3):297-305. DOI: 10.1016/j.molcel.2006.06.014
Source: PubMed


The positive transcription elongation factor b (P-TEFb) is a cyclin-dependent kinase that controls the elongation phase of transcription by RNA polymerase II (RNAPII). This process is made possible by the reversal of effects of negative elongation factors that include NELF and DSIF. In complex organisms, elongation control is critical for the regulated expression of most genes. In those organisms, the function of P-TEFb is influenced negatively by HEXIM proteins and 7SK snRNA and positively by a variety of recruiting factors. Phylogenetic analyses of the components of the human elongation control machinery indicate that the number of mechanisms utilized to regulate P-TEFb function increased as organisms developed more complex developmental patterns.

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    • "The paused Pol II elongation complex is proposed to serve as a temporal window for the recruitment of additional transcription factors and to allow well-regulated gene expression (Boettiger and Levine, 2009; Gilchrist et al., 2010; Henriques et al., 2013; Smith and Shilatifard, 2013). The transition from stalling to productive elongation requires the recruitment of cyclin-dependent kinase 9 (CDK9) containing positive transcription elongation factor b (P-TEFb) (Marshall et al., 1996), which phosphorylates DSIF, NELF, and the RPB1 CTD tail at serine 2, leading to the removal of NELF and switching DSIF from a negative to a positive elongation factor (Lin et al., 2010; Peterlin and Price, 2006; Smith and Shilatifard, 2013). Accordingly, blocking P-TEFb kinase activity with the CDK9 inhibitor flavopiridol inhibits release of paused Pol II into productive elongation (Rahl et al., 2010), but has no effect on elongating Pol II that is already in gene bodies (Jonkers et al., 2014). "
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    ABSTRACT: Although it is established that some general transcription factors are inactivated at mitosis, many details of mitotic transcription inhibition (MTI) and its underlying mechanisms are largely unknown. We have identified mitotic transcriptional activation (MTA) as a key regulatory step to control transcription in mitosis for genes with transcriptionally engaged RNA polymerase II (Pol II) to activate and transcribe until the end of the gene to clear Pol II from mitotic chromatin, followed by global impairment of transcription reinitiation through MTI. Global nascent RNA sequencing and RNA fluorescence in situ hybridization demonstrate the existence of transcriptionally engaged Pol II in early mitosis. Both genetic and chemical inhibition of P-TEFb in mitosis lead to delays in the progression of cell division. Together, our study reveals a mechanism for MTA and MTI whereby transcriptionally engaged Pol II can progress into productive elongation and finish transcription to allow proper cellular division.
    Molecular cell 11/2015; 60(3). DOI:10.1016/j.molcel.2015.09.021 · 14.02 Impact Factor
    • "Accordingly, we found higher recruitment of P-TEFb to the HIV-1 LTR following cocaine treatment. The role of P-TEFb in facilitating the elongation phase of HIV-1 transcription is well established (Bourgeois et al., 2002; Fujinaga et al., 2004; Ivanov et al., 2000; Karn, 2011; Kim et al., 2002; Parada and Roeder, 1996; Peterlin and Price, 2006; Wei et al., 1998). Hence, our results demonstrate that cocaine enhances HIV-1 gene expression by inducing both the initiation and elongation phases of HIV-1 transcription by activating NF-ĸB and MSK1. "
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    ABSTRACT: Cocaine accelerates human immunodeficiency virus (HIV-1) replication by altering specific cell-signaling and epigenetic pathways. We have elucidated the underlying molecular mechanisms through which cocaine exerts its effect in myeloid cells, a major target of HIV-1 in central nervous system (CNS). We demonstrate that cocaine treatment promotes HIV-1 gene expression by activating both nuclear factor-kappa B (NF-ĸB) and mitogen- and stress-activated kinase 1 (MSK1). MSK1 subsequently catalyzes the phosphorylation of histone H3 at serine 10, and p65 subunit of NF-ĸB at 276th serine residue. These modifications enhance the interaction of NF-ĸB with P300 and promote the recruitment of the positive transcription elongation factor b (P-TEFb) to the HIV-1 LTR, supporting the development of an open/relaxed chromatin configuration, and facilitating the initiation and elongation phases of HIV-1 transcription. Results are also confirmed in primary monocyte derived macrophages (MDM). Overall, our study provides detailed insights into cocaine-driven HIV-1 transcription and replication. Copyright © 2015 Elsevier Inc. All rights reserved.
    Virology 09/2015; 483. DOI:10.1016/j.virol.2015.03.036 · 3.32 Impact Factor
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    • "Transcription elongation is a key step in gene regulation and frequently deregulated during the progression of cancer (Luo et al., 2012). Not only transcription initiation, but also transcription elongation is important for efficient gene regulation(Peterlin and Price 2006; Luo et al., 2012). Transcription elongation is regulated by a variety of specific classes of transcription elongation factors that influence different classes of genes (Sims et al., 2004). "
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    ABSTRACT: The oncogene Tax of human T-cell leukemia virus type 1 (HTLV-1) is a potent transactivator of viral and cellular transcription. Here, we identified ELL2 as the sole transcription elongation factor to be specifically upregulated in HTLV-1-/Tax-transformed T-cells. Tax contributes to regulation of ELL2, since transient transfection of Tax increases ELL2 mRNA, Tax transactivates the ELL2 promoter, and repression of Tax results in decrease of ELL2 in transformed T-lymphocytes. However, we also measured upregulation of ELL2 in HTLV-1-transformed cells exhibiting undetectable amounts of Tax, suggesting that ELL2 can still be maintained independent of continuous Tax expression. We further show that Tax and ELL2 synergistically activate the HTLV-1 promoter, indicating that ELL2 cooperates with Tax in viral transactivation. This is supported by our findings that Tax and ELL2 accumulate in nuclear fractions and that they co-precipitate upon co-expression in transiently-transfected cells. Thus, upregulation of ELL2 could contribute to HTLV-1 gene regulation.
    Virology 09/2014; s 464–465:98–110. DOI:10.1016/j.virol.2014.06.028 · 3.35 Impact Factor
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