Insights into the function of the human P-TEFb component CDK9 in the regulation of chromatin modifications and co-transcriptional mRNA processing

Pirngruber, Judith; Shchebet, Andrei; Johnsen, Steven A.

doi:10.4161/cc.8.22.9890

Cited by 54 publications

(64 citation statements)

References 52 publications

(66 reference statements)

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“…CDK-9 has other well-characterized roles in transcriptional regulation (Pirngruber et al, 2009), and the association of CDK-9 with transcriptionally active chromatin in the adult gonad indicates it has a role in germline transcription. However, whether the essential function of CDK-9 in the germline is restricted to transcription regulation is unclear.…”

Section: Kinase Requirements In Developmentmentioning

confidence: 99%

Phosphorylation of RNA polymerase II is independent of P-TEFb in the C. elegans germline

Bowman

Ahn

et al. 2013

Development

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RNA polymerase II (Pol II) elongation in metazoans is thought to require phosphorylation of serine 2 (Ser2-P) of the Pol II C-terminal domain (CTD) by the P-TEFb complex, CDK-9/cyclin T. Another Ser2 kinase complex, CDK-12/cyclin K, which requires upstream CDK-9 activity has been identified in Drosophila and human cells. We show that regulation of Ser2-P in C. elegans soma is similar to other metazoan systems, but Ser2-P in the germline is independent of CDK-9, and largely requires only CDK-12. The observed differences are not due to differential tissue expression as both kinases and their cyclin partners are ubiquitously expressed. Surprisingly, loss of CDK-9 from germ cells has little effect on Ser2-P, yet CDK-9 is essential for germline development. By contrast, loss of CDK-12 and Ser2-P specifically from germ cells has little impact on germline development or function, although significant loss of co-transcriptional H3K36 trimethylation is observed. These results show a reduced requirement for Pol II Ser2-P in germline development and suggest that generating Ser2-P is not the essential role of CDK-9 in these cells. Transcriptional elongation in the C. elegans germline thus appears to be uniquely regulated, which may be a novel facet of germline identity.

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Section: Kinase Requirements In Developmentmentioning

confidence: 99%

Phosphorylation of RNA polymerase II is independent of P-TEFb in the C. elegans germline

Bowman

Ahn

et al. 2013

Development

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“…The SKIP homologs in Saccharomyces cerevisiae (Prp45) and Drosophila (BX42) are essential for cell viability, splicing Makarov et al 2002;Gahura et al 2009), and nuclear export of spliced mRNAs (Farny et al 2008). Although elongation factors can affect splicing indirectly through changes in the rate of elongation, and defects in cotranscriptional splicing can reduce RNAPII elongation rates in vivo (Kornblihtt 2007;Muñ oz et al 2009;Pirngruber et al 2009), SKIP is recruited to promoters as well as transcribed regions and appears to play a direct role in each process. We reported previously that SKIP associates with P-TEFb and stimulates HIV-1 Tat transcription elongation in vivo and in vitro (Brè s et al 2005).…”

mentioning

confidence: 99%

SKIP counteracts p53-mediated apoptosis via selective regulation of p21^Cip1 mRNA splicing

Chen¹,

Zhang²,

Jones³

2011

Genes Dev.

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The Ski-interacting protein SKIP/SNW1 functions as both a splicing factor and a transcriptional coactivator for induced genes. We showed previously that transcription elongation factors such as SKIP are dispensable in cells subjected to DNA damage stress. However, we report here that SKIP is critical for both basal and stress-induced expression of the cell cycle arrest factor p21Cip1 . RNAi chromatin immunoprecipitation (RNAi-ChIP) and RNA immunoprecipitation (RNA-IP) experiments indicate that SKIP is not required for transcription elongation of the gene under stress, but instead is critical for splicing and p21Cip1 protein expression. SKIP interacts with the 39 splice site recognition factor U2AF65 and recruits it to the p21 Cip1 gene and mRNA. Remarkably, SKIP is not required for splicing or loading of U2AF65 at other investigated p53-induced targets, including the proapoptotic gene PUMA. Consequently, depletion of SKIP induces a rapid down-regulation of p21Cip1 and predisposes cells to undergo p53-mediated apoptosis, which is greatly enhanced by chemotherapeutic DNA damage agents. ChIP experiments reveal that SKIP is recruited to the p21 Cip1 , and not PUMA, gene promoters, indicating that p21Cip1 gene-specific splicing is predominantly cotranscriptional. The SKIP-associated factors DHX8 and Prp19 are also selectively required for p21 Cip1 expression under stress. Together, these studies define a new step that controls cancer cell apoptosis.

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“…A role for CDK7 in the release of paused RNAPII has been attributed to its activation of CDK9 (16). CDK9 phosphorylates negative elongation factors NELF (17) and DSIF (18), thereby promoting the release of the paused RNAPII into elongation (19)(20)(21). Phosphorylation of serines at position 2 (Ser2P) in the CTD is involved in recruitment of 3= RNA-processing factors, which play a major role in the termination process (12,22,23).…”

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confidence: 99%

Cyclin-Dependent Kinase 12 Increases 3′ End Processing of Growth Factor-Induced c-FOS Transcripts

Eifler

Shao

Bartholomeeusen

et al. 2015

Molecular and Cellular Biology

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Transcriptional cyclin-dependent kinases (CDKs) regulate RNA polymerase II initiation and elongation as well as cotranscriptional mRNA processing. In this report, we describe an important role for CDK12 in the epidermal growth factor (EGF)-induced c-FOS proto-oncogene expression in mammalian cells. This kinase was found in the exon junction complexes (EJC) together with SR proteins and was thus recruited to RNA polymerase II. In cells depleted of CDK12 or eukaryotic translation initiation factor 4A3 (eIF4A3) from the EJC, EGF induced fewer c-FOS transcripts. In these cells, phosphorylation of serines at position 2 in the C-terminal domain (CTD) of RNA polymerase II, as well as levels of cleavage-stimulating factor 64 (Cstf64) and 73-kDa subunit of cleavage and polyadenylation specificity factor (CPSF73), was reduced at the c-FOS gene. These effects impaired 3′ end processing of c-FOS transcripts. Mutant CDK12 proteins lacking their Arg-Ser-rich (RS) domain or just the RS domain alone acted as dominant negative proteins. Thus, CDK12 plays an important role in cotranscriptional processing of c-FOS transcripts.

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Insights into the function of the human P-TEFb component CDK9 in the regulation of chromatin modifications and co-transcriptional mRNA processing

Cited by 54 publications

References 52 publications

Phosphorylation of RNA polymerase II is independent of P-TEFb in the C. elegans germline

Phosphorylation of RNA polymerase II is independent of P-TEFb in the C. elegans germline

SKIP counteracts p53-mediated apoptosis via selective regulation of p21^Cip1 mRNA splicing

Cyclin-Dependent Kinase 12 Increases 3′ End Processing of Growth Factor-Induced c-FOS Transcripts

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Insights into the function of the human P-TEFb component CDK9 in the regulation of chromatin modifications and co-transcriptional mRNA processing

Cited by 54 publications

References 52 publications

Phosphorylation of RNA polymerase II is independent of P-TEFb in the C. elegans germline

Phosphorylation of RNA polymerase II is independent of P-TEFb in the C. elegans germline

SKIP counteracts p53-mediated apoptosis via selective regulation of p21Cip1 mRNA splicing

Cyclin-Dependent Kinase 12 Increases 3′ End Processing of Growth Factor-Induced c-FOS Transcripts

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SKIP counteracts p53-mediated apoptosis via selective regulation of p21^Cip1 mRNA splicing