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.
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    • "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.
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    • "We therefore asked if the active subunit of the positive transcription elongation factor P-TEFb, CDK9, was recruited to p21 and puma genes. CDK9 phosphorylates the CTD of RNA Pol II primarily at serine on position two (serine 2) of its heptapeptide sequence, thereby transitioning the transcription machinery into productive transcriptional elongation[55]. Using chromatin immunoprecipitation analysis, we observed that ML-1, MANCA and A875 cell lines had comparable CDK9 recruitment at p21 and puma transcription start sites (TSS) after DNA damage (Figure 4A). This indicated that CDK9 was available to promote transcription elongation. "
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    ABSTRACT: A single nucleotide polymorphism (T to G) in the mdm2 P2 promoter, mdm2 SNP309, leads to MDM2 overexpression promoting chemotherapy resistant cancers. Two mdm2 G/G SNP309 cancer cell lines, MANCA and A875, have compromised wild-type p53 that co-localizes with MDM2 on chromatin. We hypothesized that MDM2 in these cells inhibited transcription initiation at the p53 target genes p21 and puma. Surprisingly, following etoposide treatment transcription initiation occurred at the compromised target genes in MANCA and A875 cells similar to the T/T ML-1 cell line. In all cell lines tested there was equally robust recruitment of total and initiated RNA polymerase II (Pol II). We found that knockdown of MDM2 in G/G cells moderately increased expression of subsets of p53 target genes without increasing p53 stability. Importantly, etoposide and actinomycin D treatments increased histone H3K36 trimethylation in T/T, but not G/G cells, suggesting a G/G correlated inhibition of transcription elongation. We therefore tested a chemotherapeutic agent (8-amino-adenosine) that induces p53-independent cell death for higher clinically relevant cytotoxicity. We demonstrated that T/T and G/G mdm2 SNP309 cells were equally sensitive to 8-amino-adenosine induced cell death. In conclusion for cancer cells overexpressing MDM2, targeting MDM2 may be less effective than inducing p53-independent cell death.
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