The RNA Polymerase II CTD: The Increasing Complexity of a Low-Complexity Protein Domain

Jeronimo, Célia; Collin, Pierre; Robert, François

doi:10.1016/j.jmb.2016.02.006

Cited by 118 publications

(97 citation statements)

References 144 publications

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“…Pol II CTD phosphorylation depends upon several serine-threonine kinases (Buratowski, 2009; Jeronimo et al, 2016). Cdk7 is a subunit of TFIIH, and it phosphorylates S5 and S7 in the CTD repeat.…”

Section: Resultsmentioning

confidence: 99%

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Microprocessor Recruitment to Elongating RNA Polymerase II Is Required for Differential Expression of MicroRNAs

et al. 2017

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SUMMARY The cellular abundance of mature microRNAs (miRNAs) is dictated by the efficiency of nuclear processing of primary miRNA transcripts (pri-miRNAs) into pre-miRNA intermediates. The Microprocessor complex of Drosha and DGCR8 carries this out, but it has been unclear what controls Microprocessor’s differential processing of various pri-miRNAs. Here, we show that Drosophila DGCR8 (Pasha) directly associates with the C terminal domain of the RNA polymerase II elongation complex when it is phosphorylated by the Cdk9 kinase (pTEFb). When association is blocked by loss of Cdk9 activity, a global change in pri-miRNA processing is detected. Processing of pri-miRNAs with a UGU sequence motif in their apical junction domain increases, while processing of pri-miRNAs lacking this motif decreases. Therefore, phosphorylation of RNA polymerase II recruits Microprocessor for co-transcriptional processing of non-UGU pri-miRNAs that would otherwise be poorly processed. In contrast, UGU-positive pri-miRNAs are robustly processed by Microprocessor independent of RNA polymerase association.

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Section: Resultsmentioning

confidence: 99%

“…1C) (Morris et al, 1999; Verdecia et al, 2000). The CTD is composed of a heptad sequence YSPTSPS that is repeated 52 times in human Pol II (Jeronimo et al, 2016). It is extensively modified by phosphorylation of specific residues within each repeat.…”

Section: Introductionmentioning

confidence: 99%

Microprocessor Recruitment to Elongating RNA Polymerase II Is Required for Differential Expression of MicroRNAs

et al. 2017

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“…Compared with RNAPII, which is regulated by a plethora of modifications in its C-terminal domain (21), little is known about regulation of RNAPIII activity. Several types of stress signals result in inhibition of RNAPIII activity, including nutrient stress and DNA damage, and most of these signals appear to converge on Maf1 (3).…”

Section: Sumoylation Of Rpc82 Stabilizes the Rnapiii Transcriptional mentioning

confidence: 99%

TORC1-dependent sumoylation of Rpc82 promotes RNA polymerase III assembly and activity

Chymkowitch

Aanes

et al. 2017

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

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Maintaining cellular homeostasis under changing nutrient conditions is essential for the growth and development of all organisms. The mechanisms that maintain homeostasis upon loss of nutrient supply are not well understood. By mapping the SUMO proteome in Saccharomyces cerevisiae, we discovered a specific set of differentially sumoylated proteins mainly involved in transcription. RNA polymerase III (RNAPIII) components, including Rpc53, Rpc82, and Ret1, are particularly prominent nutrient-dependent SUMO targets. Nitrogen starvation, as well as direct inhibition of the master nutrient response regulator target of rapamycin complex 1 (TORC1), results in rapid desumoylation of these proteins, which is reflected by loss of SUMO at tRNA genes. TORC1-dependent sumoylation of Rpc82 in particular is required for robust tRNA transcription. Mechanistically, sumoylation of Rpc82 is important for assembly of the RNAPIII holoenzyme and recruitment of Rpc82 to tRNA genes. In conclusion, our data show that TORC1-dependent sumoylation of Rpc82 bolsters the transcriptional capacity of RNAPIII under optimal growth conditions.I n yeast and in more complex eukaryotes, cell growth is restricted by the rate of mRNA translation and ribosome biogenesis, which depend on the transcription of ribosomal protein genes (RPGs), tRNAs and rRNAs. Synthesis of rRNA, tRNAs, and 5S rRNA represents 75% of total cellular transcription, whereas transcription of RPGs corresponds to 50% of RNA polymerase II (RNAPII) initiation events (1). These processes consume a significant portion of the cell's resources, making nutrient availability a limiting factor to cell growth and proliferation (2). The conserved rapamycin-sensitive target of rapamycin complex 1 (TORC1) is a master regulator of the cellular nutrient response (2, 3). Under nitrogen-rich conditions, TORC1 promotes growth-related processes, like protein synthesis, ribosome biogenesis, and tRNA synthesis, while inhibiting catabolic processes, like autophagy (2). Conversely, inhibition of TORC1 activity by nitrogen depletion (or addition of the TORC1 inhibitor rapamycin) results in a metabolic switch from anabolism to catabolism, which involves many cellular processes, including down-regulation of transcription of RPGs, rRNA and tRNA genes (2, 3).A key downstream target of TORC1 in regulation of tRNA transcription is the conserved RNAPIII inhibitor Maf1, which is phosphorylated and maintained in the cytoplasm under nitrogenrich conditions (2, 3). Maf1 becomes hypophosphorylated under conditions that inhibit TORC1, allowing it to enter the nucleus where it associates with TFIIIB. The interaction between Maf1 and TFIIIB prevents the recruitment of RNAPIII and precludes transcription reinitiation at 5S rRNA and tRNA genes (4, 5). However, expression of an unphosphorylatable maf1 mutant does not completely repress tRNA expression in nutrient-replete cells (6), suggesting that dephosphorylation of Maf1 alone is not sufficient to fully inhibit RNAPIII. Indeed, inhibition of TORC1 also results in phospho...

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“…CDK12 is a cyclin dependent kinase involved in the regulation of transcription and in post-transcriptional mRNA processing through the phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (RNAPII)47. CDK12 has been implicated in modulating the transcription of long and complex genes, i.e.…”

Section: Discussionmentioning

confidence: 99%

The impact of DNA damage response gene polymorphisms on therapeutic outcomes in late stage ovarian cancer

Guffanti

Fruscio

Rulli

et al. 2016

Sci Rep

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Late stage epithelial ovarian cancer has a dismal prognosis. Identification of pharmacogenomic markers (i.e. polymorphisms) to stratify patients to optimize individual therapy is of paramount importance. We here report the retrospective analysis of polymorphisms in 5 genes (ATM, ATR, Chk1, Chk2 and CDK12) involved in the cellular response to platinum in a cohort of 240 cancer patients with late stage ovarian cancer. The aim of the present study was to evaluate associations between the above mentioned SNPs and patients’ clinical outcomes: overall survival (OS) and progression free survival (PFS). None of the ATM, ATR, Chk1 and Chk2 polymorphisms was found to significantly affect OS nor PFS in this cohort of patients. Genotype G/G of CDK12 polymorphism (rs1054488) predicted worse OS and PFS than the genotype A/A-A/G in univariate analysis. The predictive value was lost in the multivariate analysis. The positive correlation observed between this polymorphism and age, grade and residual tumor may explain why the CDK12 variant was not confirmed as an independent prognostic factor in multivariate analysis.The importance of CDK12 polymorphism as possible prognostic biomarker need to be confirmed in larger ovarian cancer cohorts, and possibly in other cancer population responsive to platinum agents.

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The RNA Polymerase II CTD: The Increasing Complexity of a Low-Complexity Protein Domain

Cited by 118 publications

References 144 publications

Microprocessor Recruitment to Elongating RNA Polymerase II Is Required for Differential Expression of MicroRNAs

Microprocessor Recruitment to Elongating RNA Polymerase II Is Required for Differential Expression of MicroRNAs

TORC1-dependent sumoylation of Rpc82 promotes RNA polymerase III assembly and activity

The impact of DNA damage response gene polymorphisms on therapeutic outcomes in late stage ovarian cancer

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