PNUTS/PP1 regulates RNAPII-mediated gene expression and is necessary for developmental growth

Autor: Luke Alphey, Emese Vissi, Anita Ciurciu, Neville Cobbe, Vincent Jonchere, Peter Glenday, Daimark Bennett, Andreii Rudenko, Olga Vasieva, Nick Lansdale, Louise Duncalf
Přispěvatelé: University of Liverpool, Picower Institute for Learning and Memory, Rudenko, Andrii
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Cancer Research
Transcription
Genetic
lcsh:QH426-470
Molecular Sequence Data
Embryonic Development
RNA-binding protein
RNA polymerase II
environment and public health
Oxitec Limited
03 medical and health sciences
0302 clinical medicine
Transcription (biology)
Catalytic Domain
Protein Phosphatase 1
Gene expression
Genetics
Transcriptional regulation
Animals
Phosphorylation
Molecular Biology
Gene
Genetics (clinical)
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
Regulation of gene expression
0303 health sciences
biology
[SDV.BA]Life Sciences [q-bio]/Animal biology
fungi
Gene Expression Regulation
Developmental
RNA-Binding Proteins
biology.organism_classification
United Kingdom
Protein Structure
Tertiary
DNA-Binding Proteins
enzymes and coenzymes (carbohydrates)
lcsh:Genetics
Drosophila melanogaster
030220 oncology & carcinogenesis
biology.protein
RNA Polymerase II
Oxford
Research Article
Zdroj: PLoS Genetics, Vol 9, Iss 10, p e1003885 (2013)
PLoS Genetics
PLoS Genetics, Public Library of Science, 2013, 9 (10), pp.e1003885. ⟨10.1371/journal.pgen.1003885⟩
PLoS
ISSN: 1553-7404
1553-7390
Popis: In multicellular organisms, tight regulation of gene expression ensures appropriate tissue and organismal growth throughout development. Reversible phosphorylation of the RNA Polymerase II (RNAPII) C-terminal domain (CTD) is critical for the regulation of gene expression states, but how phosphorylation is actively modified in a developmental context remains poorly understood. Protein phosphatase 1 (PP1) is one of several enzymes that has been reported to dephosphorylate the RNAPII CTD. However, PP1's contribution to transcriptional regulation during animal development and the mechanisms by which its activity is targeted to RNAPII have not been fully elucidated. Here we show that the Drosophila orthologue of the PP1 Nuclear Targeting Subunit (dPNUTS) is essential for organismal development and is cell autonomously required for growth of developing tissues. The function of dPNUTS in tissue development depends on its binding to PP1, which we show is targeted by dPNUTS to RNAPII at many active sites of transcription on chromosomes. Loss of dPNUTS function or specific disruption of its ability to bind PP1 results in hyperphosphorylation of the RNAPII CTD in whole animal extracts and on chromosomes. Consistent with dPNUTS being a global transcriptional regulator, we find that loss of dPNUTS function affects the expression of the majority of genes in developing 1st instar larvae, including those that promote proliferative growth. Together, these findings shed light on the in vivo role of the PNUTS-PP1 holoenzyme and its contribution to the control of gene expression during early Drosophila development.
Author Summary During development, cells rely on appropriate patterns of gene expression to regulate metabolism in order to meet cellular demands and maintain rapid tissue growth. Conversely, dysregulation of gene expression is critical in various disease states, such as cancer, and during ageing. A key mechanism that is ubiquitously employed to control gene expression is reversible phosphorylation, a molecular switch that is used to regulate the activity of the transcriptional machinery. Here we identify an enzyme that binds to and regulates the phosphorylation state of RNA Polymerase II, a central component of the general transcription machinery. We also show that an essential role of this enzyme is to support normal patterns of gene expression that facilitate organismal growth. These findings are not only of relevance to the understanding of normal enzyme function but may also assist in the development of therapeutic strategies for the treatment of aberrant patterns of gene expression that occur during ageing and disease progression.
Databáze: OpenAIRE
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