“Cotranscriptionality”: The Transcription Elongation Complex as a Nexus for Nuclear Transactions

Perales, Roberto; Bentley, David L.

doi:10.1016/j.molcel.2009.09.018

Cited by 320 publications

(364 citation statements)

References 135 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%

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%

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

2012

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“…5 The CTD mediates coupling of transcription with pre-mRNA processing [6][7][8][9][10] by acting as a "landing pad" for recruitment of RNA processing factors to the transcription site, 11 thus facilitating co-transcriptional pre-mRNA processing (For a review see refs. [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Localization of RNAPII and 3′ end formation factor CstF subunits onC. elegansgenes and operons

2016

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Transcription termination is mechanistically coupled to pre-mRNA 3 0 end formation to prevent transcription much beyond the gene 3 0 end. C. elegans, however, engages in polycistronic transcription of operons in which 3 0 end formation between genes is not accompanied by termination. We have performed RNA polymerase II (RNAPII) and CstF ChIP-seq experiments to investigate at a genome-wide level how RNAPII can transcribe through multiple poly-A signals without causing termination. Our data shows that transcription proceeds in some ways as if operons were composed of multiple adjacent single genes. Total RNAPII shows a small peak at the promoter of the gene cluster and a much larger peak at 3 0 ends. These 3 0 peaks coincide with maximal phosphorylation of Ser2 within the C-terminal domain (CTD) of RNAPII and maximal localization of the 3 0 end formation factor CstF. This pattern occurs at all 3 0 ends including those at internal sites in operons where termination does not occur. Thus the normal mechanism of 3 0 end formation does not always result in transcription termination. Furthermore, reduction of CstF50 by RNAi did not substantially alter the pattern of CstF64, total RNAPII, or Ser2 phosphorylation at either internal or terminal 3 0 ends. However, CstF50 RNAi did result in a subtle reduction of CstF64 binding upstream of the site of 3 0 cleavage, suggesting that the CstF50/CTD interaction may facilitate bringing the 3 0 end machinery to the transcription complex.

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“…Transcription and splicing are coupled processes (9,10). Splicing occurs cotranscriptionally, and multiple lines of evidence indicate that transcription elongation and splicing influence each other.…”

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confidence: 99%

Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing

Jimeno-González

Payán-Bravo

Muñoz-Cabello

et al. 2015

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

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RNA polymerase II (RNAPII) transcription elongation is a highly regulated process that greatly influences mRNA levels as well as pre-mRNA splicing. Despite many studies in vitro, how chromatin modulates RNAPII elongation in vivo is still unclear. Here, we show that a decrease in the level of available canonical histones leads to more accessible chromatin with decreased levels of canonical histones and variants H2A.X and H2A.Z and increased levels of H3.3. With this altered chromatin structure, the RNAPII elongation rate increases, and the kinetics of pre-mRNA splicing is delayed with respect to RNAPII elongation. Consistent with the kinetic model of cotranscriptional splicing, the rapid RNAPII elongation induced by histone depletion promotes the skipping of variable exons in the CD44 gene. Indeed, a slowly elongating mutant of RNAPII was able to rescue this defect, indicating that the defective splicing induced by histone depletion is a direct consequence of the increased elongation rate. In addition, genome-wide analysis evidenced that histone reduction promotes widespread alterations in pre-mRNA processing, including intron retention and changes in alternative splicing. Our data demonstrate that premRNA splicing may be regulated by chromatin structure through the modulation of the RNAPII elongation rate. T he transcription process comprises several steps, including preinitiation complex formation, promoter escape, elongation, and termination (1). Recent reports indicate that elongation rates of RNA polymerase II (RNAPII) in mammals range from 0.5 to 4 kb/min, but which factors are responsible for these differences is still unclear (2-4). One obvious candidate for affecting transcription elongation is chromatin structure. The building block of chromatin is the nucleosome comprising 147 bp of DNA around a histone octamer formed by two H2A-H2B dimers and one H3-H4 tetramer. In vitro experiments have demonstrated that nucleosomes are a barrier for RNAPII transcription elongation (5, 6). We have reported that a nucleosome positioned in the body of a transcription unit impairs RNAPII progression in vivo (7). Furthermore, Weber et al. (8) have shown recently that RNAPII stalls in vivo at the entry site of essentially every transcribed nucleosome in Drosophila. Despite this evidence, it is still unclear whether changes in chromatin structure in different regions of a gene or between different genes can regulate the rate of transcription elongation.Transcription and splicing are coupled processes (9, 10). Splicing occurs cotranscriptionally, and multiple lines of evidence indicate that transcription elongation and splicing influence each other. On one hand, it has been suggested that splicing factors are recruited to the template by the transcription machinery (11, 12). On the other hand, the rate of RNAPII elongation influences splicing. The kinetic model proposes that a slow elongation rate facilitates weak splice-site recognition, promoting the inclusion of alternative exons (13, 14). However, recent studies have ex...

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“Cotranscriptionality”: The Transcription Elongation Complex as a Nexus for Nuclear Transactions

Cited by 320 publications

References 135 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

Localization of RNAPII and 3′ end formation factor CstF subunits onC. elegansgenes and operons

Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing

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