Pausing for thought: Disrupting the early transcription elongation checkpoint leads to developmental defects and tumourigenesis

Jennings, Barbara

doi:10.1002/bies.201200179

Cited by 15 publications

(10 citation statements)

References 88 publications

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“…In particular, the defects caused by Spt5 mutations that impact cell viability or organismal development are poorly understood. Interestingly, several mutations that lead to developmental defects are predicted to destabilize Spt5 structure, and careful examination of Spt5 levels in missense mutations reveals that many are protein hypomorphs Jennings 2013;Bernecky et al 2017). Thus, reduced cellular levels of Spt5 appear sufficient to cause cell type-or conditionspecific defects.…”

Section: Spt5 and The Dsif Complexmentioning

confidence: 99%

Promoter-proximal pausing of RNA polymerase II: a nexus of gene regulation

2019

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Precise spatio-temporal control of gene activity is essential for organismal development, growth, and survival in a changing environment. Decisive steps in gene regulation involve the pausing of RNA polymerase II (Pol II) in early elongation, and the controlled release of paused polymerase into productive RNA synthesis. Here we describe the factors that enable pausing and the events that trigger Pol II release into the gene. We also discuss open questions in the field concerning the stability of paused Pol II, nucleosomes as obstacles to elongation, and potential roles of pausing in defining the precision and dynamics of gene expression.Cell type-and condition-specific patterns of gene expression involve tight control of multiple steps in the transcription cycle. Early regulatory events govern the association of DNA-binding transcription factors (TFs) with their target motifs and the recruitment of RNA polymerase II (Pol II) and general TFs (GTFs) to the promoter region of a gene. These events enable transcription initiation and the synthesis of a short, nascent RNA. However, Pol II then pauses promoter-proximally, awaiting further signals before entering the gene body. The fate of the paused early elongation complex is absolutely decisive for gene output. If paused Pol II successfully transitions into productive elongation, a functional full-length mRNA can be made. However, a failure in the maturation of paused Pol II toward productive RNA synthesis short circuits the process of gene expression. Thus, understanding the factors that govern stable Pol II pausing and release are of paramount importance toward an appreciation of gene regulation in human health and disease.

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Section: Spt5 and The Dsif Complexmentioning

confidence: 99%

Promoter-proximal pausing of RNA polymerase II: a nexus of gene regulation

2019

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“…This in turn facilitates release of paused RNA Pol II aiding in productive elongation. CDK9 also acts directly on RNA Pol II, phosphorylating it on S5 in the C-terminal domain, a known mark of elongating RNA Pol II [26]. As the P-TEFb complex is normally rendered inactive through sequestration by 7SK snRNP complex, we hypothesized that overexpressing CDK9 might bypass normal regulation of pausing, leading to inactivation of NELF complex and RNA Pol II release.…”

Section: Cdk9 Is Required For Yki Mediated Tumorigenesismentioning

confidence: 99%

Promoter proximal pausing limits Yki-induced tumorous growth in Drosophila

Nagarkar

Wasnik

Govada

et al. 2019

Preprint

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Promoter proximal pausing (PPP) of RNA Polymerase II has emerged as a crucial ratelimiting-step in the regulation of gene expression. Regulation of PPP is brought about by complexes 7SK snRNP, P-TEFb (Cdk9/cycT) and the Negative Elongation Factor (NELF) which are highly conserved from Drosophila to humans. Here we show that RNAi-mediated depletion of bin3 or Hexim of the 7SK snRNP complex or depletion of individual components of the NELF complex enhance Yki-driven growth leading to neoplastic transformation of Drosophila wing imaginal discs. We also show that increased CDK9 expression cooperates with Yki, in driving neoplastic growth. Interestingly, over-expression of CDK9 on its own or in the background of depletion of one of the components of 7SK snRNP or the NELF complex necessarily and specifically needed Yki over-expression to cause tumorous growth. Genome-wide gene expression analyses suggested that deregulation of protein homeostasis is associated with tumorous growth of wing imaginal discs. As both Fat/Hippo/Yki pathway and PPP are highly conserved, our observations may provide insights into mechanisms of oncogenic function of YAP, the orthologue of Yki in human.

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“…When this process fails it leads to death or severe defects during development and contributes to cancer pathogenesis in adult animals [1].…”

Section: Introductionmentioning

confidence: 99%

Pleiohomeotic Interacts with the Core Transcription Elongation Factor Spt5 to Regulate Gene Expression in Drosophila

2013

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The early elongation checkpoint regulated by Positive Transcription Elongation Factor b (P-TEFb) is a critical control point for the expression of many genes. Spt5 interacts directly with RNA polymerase II and has an essential role in establishing this checkpoint, and also for further transcript elongation. Here we demonstrate that Drosophila Spt5 interacts both physically and genetically with the Polycomb Group (PcG) protein Pleiohomeotic (Pho), and the majority of Pho binding sites overlap with Spt5 binding sites across the genome in S2 cells. Our results indicate that Pho can interact with Spt5 to regulate transcription elongation in a gene specific manner.

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Pausing for thought: Disrupting the early transcription elongation checkpoint leads to developmental defects and tumourigenesis

Cited by 15 publications

References 88 publications

Promoter-proximal pausing of RNA polymerase II: a nexus of gene regulation

Promoter-proximal pausing of RNA polymerase II: a nexus of gene regulation

Promoter proximal pausing limits Yki-induced tumorous growth in Drosophila

Pleiohomeotic Interacts with the Core Transcription Elongation Factor Spt5 to Regulate Gene Expression in Drosophila

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