Cracking the RNA polymerase II CTD code

Egloff, Sylvain; Murphy, Shona

doi:10.1016/j.tig.2008.03.008

Cited by 343 publications

(364 citation statements)

References 82 publications

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“…It is suggested that different combinations of Ser2, Ser5 and Ser7 phosphorylations as well as proline isomerization constitute a 'CTD code' , which orchestrates transcription with pre-mRNA processing, histone modification and spliceosomal subunit arrangements [3][4][5][6]54 . The unexpected finding that P-TEFb is a Ser5 CTD kinase with a preference for Ser7 pre-phosphorylations to generate Ser5/Ser7 double-phosphorylation marks requires further structural and functional investigations on the multifaceted CTD phosphorylation patterns and their corresponding recognitions.…”

Section: Y S P T S P S Y S P T S P S Y S P T S P Smentioning

confidence: 99%

“…High levels of Ser7 and Ser5 phosphorylations occur at the transcription start site, whereas Ser2 phosphorylation levels increase until they reach their peak about 600-1,000 nucleotides downstream of the start site 20 . These modifications suggest a dual gradient model for increasing Ser2 and decreasing Ser5 phosphorylation across genes that regulate transcription 3,4 . In addition to these serine phosphorylations, arginine methylation at one specific residue of the CTD was shown to lead to misregulation of snRNAs as well as small nucleolar RNAs expression 21 .…”

mentioning

confidence: 97%

“…Release from this block requires the positive transcription elongation factor P-TEFb 2 , which is a heterodimer composed of the cyclin-dependent kinase Cdk9 and the regulatory subunit Cyclin T. P-TEFb mediates the transition from transcription initiation to productive elongation of pre-mRNA transcripts by phosphorylation of the carboxy-terminal domain (CTD) of the largest subunit of RNAPII. In humans, the CTD comprises 52 repeats of the consensus sequence Y 1 S 2 P 3 T 4 S 5 P 6 S 7 that exhibits only some variations from the strict consensus towards the C-terminus [3][4][5][6][7] . Phosphorylation of Ser5 by Cdk7 and Cdk8 kinases of TFIIH and the mediator complex, respectively, has been described to be concomitant with transcription initiation, whereas Cdk9 of P-TEFb is suggested to phosphorylate Ser2, which marks the elongation phase of transcription [3][4][5][6][7][8] .…”

mentioning

confidence: 99%

“…In humans, the CTD comprises 52 repeats of the consensus sequence Y 1 S 2 P 3 T 4 S 5 P 6 S 7 that exhibits only some variations from the strict consensus towards the C-terminus [3][4][5][6][7] . Phosphorylation of Ser5 by Cdk7 and Cdk8 kinases of TFIIH and the mediator complex, respectively, has been described to be concomitant with transcription initiation, whereas Cdk9 of P-TEFb is suggested to phosphorylate Ser2, which marks the elongation phase of transcription [3][4][5][6][7][8] . In addition, Ser7 of the CTD can also be phosphorylated, which has been linked to small nuclear RNAs (snRNA) transcription and recruitment of the integrator complex [9][10][11][12][13] .…”

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confidence: 99%

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Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition

2012

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Phosphorylation of RnA polymerase II carboxy-terminal domain (CTD) in hepta-repeats YsPTsPs regulates eukaryotic transcription. Whereas ser5 is phosphorylated in the initiation phase, ser2 phosphorylation marks the elongation state. Here we show that the positive transcription elongation factor P-TEFb is a ser5 CTD kinase that is unable to create ser2/ser5 double phosphorylations, while it exhibits fourfold higher activity on a CTD substrate prephosphorylated at ser7 compared with the consensus hepta-repeat or the YsPTsPK variant. mass spectrometry reveals an equal number of phosphorylations to the number of heptarepeats provided, yet the mechanism of phosphorylation is distributive despite the repetitive nature of the substrate. Inhibition of P-TEFb activity is mediated by two regions in Hexim1 that act synergistically on Cdk9 and Cyclin T1. HIV-1 Tat/TAR abrogates Hexim1 inhibition to stimulate transcription of viral genes but does not change the substrate specificity. Together, these results provide insight into the multifaceted pattern of CTD phosphorylation.

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Section: Y S P T S P S Y S P T S P S Y S P T S P Smentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition

2012

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“…Further transcript elongation is associated with increased phosphorylation of serine 2 (Ser2P), initially occurring as a Ser2P/Ser5P form of the CTD repeat, and later transitioning to a Ser2P form (Komarnitsky et al, 2000;Egloff and Murphy, 2008). Ser2P is mediated by CDK9, which is recruited via a Ser5P-dependent mechanism (Qiu et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Two Distinct Roles of ARABIDOPSIS HOMOLOG OF TRITHORAX1 (ATX1) at Promoters and within Transcribed Regions of ATX1-Regulated Genes

2011

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The Arabidopsis thaliana trithorax-like protein, ATX1, shares common structural domains, has similar histone methyltransferase (HMT) activity, and belongs in the same phylogenetic subgroup as its animal counterparts. Most of our knowledge of the role of HMTs in trimethylating lysine 4 of histone H3 (H3K4me3) in transcriptional regulation comes from studies of yeast and mammalian homologs. Little is known about the mechanism by which ATX1, or any other HMT of plant origin, affects transcription. Here, we provide insights into how ATX1 influences transcription at regulated genes, playing two distinct roles. At promoters, ATX1 is required for TATA binding protein (TBP) and RNA Polymerase II (Pol II) recruitment. In a subsequent event, ATX1 is recruited by a phosphorylated form of Pol II to the +300-bp region of transcribed sequences, where it trimethylates nucleosomes. In support of this model, inhibition of phosphorylation of the C-terminal domain of Pol II reduced the amounts of H3K4me3 and ATX1 bound at the +300-nucleotide region. Importantly, these changes did not reduce the occupancy of ATX1, TBP, or Pol II at promoters. Our results indicate that ATX1 affects transcription at target genes by a mechanism distinct from its ability to trimethylate H3K4 within genes.

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Structural basis for the recognition of the S2, S5‐phosphorylated RNA polymerase II CTD by the mRNA anti‐terminator protein hSCAF4

et al. 2021

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The C‐terminal domain (CTD) of RNA polymerase II serves as a binding platform for numerous enzymes and transcription factors involved in nascent RNA processing and the transcription cycle. The S2, S5‐phosphorylated CTD is recognized by the transcription factor SCAF4, which functions as a transcription anti‐terminator by preventing early mRNA transcript cleavage and polyadenylation. Here, we measured the binding affinities of differently modified CTD peptides by hSCAF4 and solved the complex structure of the hSCAF4‐CTD‐interaction domain (CID) bound to a S2, S5‐quadra‐phosphorylated CTD peptide. Our results revealed that the S2, S5‐quadra‐phosphorylated CTD peptide adopts a trans conformation and is located in a positively charged binding groove of hSCAF4‐CID. Although hSCAF4‐CID has almost the same binding pattern to the CTD as other CID‐containing proteins, it preferentially binds to the S2, S5‐phosphorylated CTD. Our findings provide insight into the regulatory mechanism of hSCAF4 in transcription termination.

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Cracking the RNA polymerase II CTD code

Cited by 343 publications

References 82 publications

Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition

Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition

Two Distinct Roles of ARABIDOPSIS HOMOLOG OF TRITHORAX1 (ATX1) at Promoters and within Transcribed Regions of ATX1-Regulated Genes

Structural basis for the recognition of the S2, S5‐phosphorylated RNA polymerase II CTD by the mRNA anti‐terminator protein hSCAF4

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