Bur1/Bur2 and the Ctk Complex in Yeast: The Split Personality of Mammalian P-TEFb

Wood, Adam; Shilatifard, Ali

doi:10.4161/cc.5.10.2769

Cited by 62 publications

(71 citation statements)

References 40 publications

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“…However, as previously discussed by Wood and Shilatifard, there are both important similarities and distinctions between the yeast and human P-TEFb complexes. 35 Our results expand upon the many studies in yeast and demonstrate important distinctions between yeast and mammals. We have shown that CDK9 not only regulates H3K36me3, which is a characteristic of the yeast CTD kinase Ctk1, but also controls H2Bub1 and H3K4me3 which is a function of Bur1 in yeast.…”

Section: Similarities and Distinctions Between P-tefb Function In Yeasupporting

confidence: 81%

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

Pirngruber¹,

Shchebet²,

Johnsen³

2009

Cell Cycle

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C yclin-dependent kinase-9 (CDK9) was originally characterized as a transcription elongation factor which regulates RNA Polymerase II (RNAPII) activity following transcriptional initiation. However, recent evidence from a number of studies have shown that CDK9 plays an important role in regulating not only RNAPII activity but also cotranscriptional histone modification and mRNA processing events such as splicing and 3' end processing. Importantly, our previous work and the work presented here demonstrate that CDK9 functions to guide a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3. This function appears to be dependent upon not only the phosphorylation of the RNA Polymerase II C-terminal domain but also upon other CDK9 targets such as the Suppressor of Ty Homolog-5 (SUPT5H), Negative Elongation Factor-E (NELF-E) and probably the human Rad6 homolog UBE2A. We provide a working model by which CDK9 may control co-transcriptional replication-dependent histone mRNA 3' end processing in an H2Bub1 and H3K4me3-dependent manner and uncover new and important differences between the functions of human CDK9 and its yeast counterparts Ctk1 and Bur1.

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Section: Similarities and Distinctions Between P-tefb Function In Yeasupporting

confidence: 81%

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

Pirngruber¹,

Shchebet²,

Johnsen³

2009

Cell Cycle

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“…BUR kinase also phosphorylates Rad6, leading to the ubiquitination of histone H2B on K123 (31,51). Because K123 ubiquitination also has a positive effect on elongation by RNAPII (52), it could be that it is H2B ubiquitination rather than Spt5 CTR phosphorylation that helps overcome the inhibiting effects of Set2 and Rpd3S on elongation.…”

Section: Discussionmentioning

confidence: 99%

Control of transcriptional elongation and cotranscriptional histone modification by the yeast BUR kinase substrate Spt5

Zhou

Kuo²,

Fillingham³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

140

184

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Elongation by RNA polymerase II (RNAPII) is a finely regulated process in which many elongation factors contribute to gene regulation. Among these factors are the polymerase-associated factor (PAF) complex, which associates with RNAPII, and several cyclin-dependent kinases, including positive transcription elongation factor b (P-TEFb) in humans and BUR kinase (Bur1-Bur2) and C-terminal domain (CTD) kinase 1 (CTDK1) in Saccharomyces cerevisiae. An important target of P-TEFb and CTDK1, but not BUR kinase, is the CTD of the Rpb1 subunit of RNAPII. Although the essential BUR kinase phosphorylates Rad6, which is required for histone H2B ubiquitination on K123, Rad6 is not essential, leaving a critical substrate(s) of BUR kinase unidentified. Here we show that BUR kinase is important for the phosphorylation in vivo of Spt5, a subunit of the essential yeast RNAPII elongation factor Spt4/Spt5, whose human orthologue is DRB sensitivity-inducing factor. BUR kinase can also phosphorylate the C-terminal region (CTR) of Spt5 in vitro. Like BUR kinase, the Spt5 CTR is important for promoting elongation by RNAPII and recruiting the PAF complex to transcribed regions. Also like BUR kinase and the PAF complex, the Spt5 CTR is important for histone H2B K123 monoubiquitination and histone H3 K4 and K36 trimethylation during transcription elongation. Our results suggest that the Spt5 CTR, which contains 15 repeats of a hexapeptide whose consensus sequence is S[T/A]WGG[A/Q], is a substrate of BUR kinase and a platform for the association of proteins that promote both transcription elongation and histone modification in transcribed regions.longation by RNA polymerase II (RNAPII) involves a number of factors that interact directly or indirectly with the enzyme (1). Among these RNAPII-interacting proteins in the budding yeast Saccharomyces cerevisiae are the RNA chain cleavage factor TFIIS, the chromatin assembly factor Spt16/Pob3 (known as FACT in higher eukaryotes), the polymerase-associated factor (PAF) complex, and Spt4/Spt5, which is orthologous to DRB sensitivityinducing factor (DSIF) in humans. These factors can associate with the transcription complex from the promoter-proximal region to the cleavage and polyadenylation signal or the transcription termination site. In higher eukaryotes, DSIF and the negative elongation factor (NELF), which appears not to exist in S. cerevisiae, restrain elongation by RNAPII soon after initiation (2). As a consequence, many inactive genes in higher eukaryotes have ''paused'' or ''poised'' RNAPII molecules downstream of their promoters (3).An important event during elongation by RNAPII is phosphorylation of the heptapeptide repeats (consensus sequence YSPTSPS) in the C-terminal domain (CTD) of Rpb1, the largest subunit of RNAPII (4). Phosphorylation on S5 of the CTD repeats is catalyzed by the Kin28 subunit (CDK7 in humans) of the general initiation factor TFIIH. S5 phosphorylation tends to decline across yeast transcription units (5, 6) and is reversed by the Ssu72 subunit (7) of the cleavage an...

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“…The Bur complex implements CTD phosphorylation early in the transcription cycle, while the Ctk complex implements CTD phosphorylation during the elongation phase of RNA Pol II (9). CDK9 was long considered to be the only CTD Ser2 kinase in metazoans, but recently the Drosophila dCdk12/dCyclin K complex was shown to be the major CTD Ser2 kinase implementing Ser2 phosphorylation during the elongation stage, analogous to the S. cerevisiae Ctk1/2 complex (10).…”

mentioning

confidence: 99%

Characterization of Human Cyclin-Dependent Kinase 12 (CDK12) and CDK13 Complexes in C-Terminal Domain Phosphorylation, Gene Transcription, and RNA Processing

Liang

Gào

Gilmore

et al. 2015

Molecular and Cellular Biology

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167

182

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c Cyclin-dependent kinase 9 (CDK9) and CDK12 have each been demonstrated to phosphorylate the RNA polymerase II C-terminal domain (CTD) at serine 2 of the heptad repeat, both in vitro and in vivo. CDK9, as part of P-TEFb and the super elongation complex (SEC), is by far the best characterized of CDK9, CDK12, and CDK13. We employed both in vitro and in vivo assays to further investigate the molecular properties of CDK12 and its paralog CDK13. We isolated Flag-tagged CDK12 and CDK13 and found that they associate with numerous RNA processing factors. Although knockdown of CDK12, CDK13, or their cyclin partner CCNK did not affect the bulk CTD phosphorylation levels in HCT116 cells, transcriptome sequencing (RNA-seq) analysis revealed that CDK12 and CDK13 losses in HCT116 cells preferentially affect expression of DNA damage response and snoRNA genes, respectively. CDK12 and CDK13 depletion also leads to a loss of expression of RNA processing factors and to defects in RNA processing. These findings suggest that in addition to implementing CTD phosphorylation, CDK12 and CDK13 may affect RNA processing through direct physical interactions with RNA processing factors and by regulating their expression.T he largest subunit of RNA polymerase II (Pol II), Rpb1, contains a C-terminal domain (CTD) consisting of 52 heptad repeats of the YSPTSPS consensus sequence in humans (1). The CTD is phosphorylated within these repeats, including at serines 2, 5, and 7 (Ser2, Ser5, and Ser7, respectively) (2). The CTD serves as a phosphorylation-regulated platform for the recruitment of transcription factors, RNA processing factors, and chromatin modifiers, which affect mRNA synthesis, cotranscriptional processing, and histone modifications during the transcription cycle (3).The CTD undergoes a cycle of phosphorylation and dephosphorylation during the transcription cycle of initiation, elongation, and termination (4). During transcription initiation and early transcription, Ser5 of the CTD is phosphorylated by the cyclin-dependent kinase 7 (CDK7) subunit of the basal transcription factor TFIIH (2, 5). The positive transcription elongation factor, P-TEFb (comprised of CDK9 and cyclin T), regulates transcription elongation through phosphorylation of the CTD at Ser2 (6). P-TEFb also phosphorylates negative elongation factor (NELF) (7) and DRB sensitivity-inducing factor (DSIF) (8) during the transition to productive elongation.In the budding yeast Saccharomyces cerevisiae, there are two complexes for CTD Ser2 phosphorylation: the Bur1/Bur2 complex and the Ctk1/Ctk2/Ctk3 (CTDK) complex. The Bur complex implements CTD phosphorylation early in the transcription cycle, while the Ctk complex implements CTD phosphorylation during the elongation phase of RNA Pol II (9). CDK9 was long considered to be the only CTD Ser2 kinase in metazoans, but recently the Drosophila dCdk12/dCyclin K complex was shown to be the major CTD Ser2 kinase implementing Ser2 phosphorylation during the elongation stage, analogous to the S. cerevisiae Ctk1/2 complex (10). In ...

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Bur1/Bur2 and the Ctk Complex in Yeast: The Split Personality of Mammalian P-TEFb

Cited by 62 publications

References 40 publications

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

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

Control of transcriptional elongation and cotranscriptional histone modification by the yeast BUR kinase substrate Spt5

Characterization of Human Cyclin-Dependent Kinase 12 (CDK12) and CDK13 Complexes in C-Terminal Domain Phosphorylation, Gene Transcription, and RNA Processing

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