Dissecting Cyclin-dependent Kinase Functions in MRNA Quality Control in Fission Yeast PDF Download
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Author: Courtney Virginia St. Amour
Publisher:
ISBN:
Category :
Languages : en
Pages : 282
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Book Description
RNA Polymerase (Pol) II transcribes protein-coding genes in eukaryotic cells. Transcription by Pol II is coordinated with processes through the carboxyl-terminal domain (CTD) of its largest subunit, Rpb1. Cyclin-dependent kinases (CDKs) phosphorylate CTD heptad repeats to influence their binding properties and thereby govern co-transcriptional mRNA processing. Transcription factor (TF) IIH-associated Cdk7 phosphorylates Ser5 residues to recruit capping enzymes, while Cdk9 promotes elongation by phosphorylating the CTD and the processivity factor Spt5. I examined the functions of these essential kinases in fission yeast in a putative mRNA quality control mechanism that could ensure that only fully capped transcripts are elongated. I found that Cdk9 forms a constitutive and stable complex with the cyclin Pch1 and the 5'-cap methyltransferase Pcm1 in vivo. Using chemical genetics, we showed that Mcs6 activity is required to recruit the Cdk9-Pch1-Pcm1 complex to a subset of CDK-dependent genes. In vitro, I showed that phosphorylation of the CTD by Mcs6 stimulates subsequent phosphorylation by Cdk9. Together, these observations support a model in which Mcs6 and Cdk9 act sequentially to coordinate elongation and capping of select pre-mRNAs. To test that model, I undertook a functional dissection of the fission yeast Cdk9-Pch1-Pcm1 complex. I show that a Cdk9 carboxyl-terminal extension, distinct from the catalytic domain, mediates binding to Pcm1 and the Pol II CTD. Removal of this segment leads to growth defects and transcriptional deficiencies. These phenotypes are suppressed by Pcm1 overproduction, suggesting that normal transcript elongation and gene expression depend on physical linkage between Cdk9 and Pcm1. The extension is dispensable, however, for recognition by Cdk9 of CTD substrates "primed" by Mcs6. Cdk9 prefers CTD peptides phosphorylated at Ser7 over unmodified repeats. In vivo, Ser7 phosphorylation depends on Mcs6 activity, suggesting a mechanism to order transcriptional CDK functions, independent of chromatin recruitment. Therefore, fission yeast Cdk9 comprises a catalytic domain sufficient for primed substrate recognition, and a multivalent recruitment module that couples transcription with capping. Together, these results support a proposed model whereby CTD phosphorylation by Mcs6 stimulates subsequent Cdk9 activity and the Cdk9/Pcm1 complex serves to coordinate capping with transcript elongation, thereby protecting mRNA quality.
Author: Courtney Virginia St. Amour
Publisher:
ISBN:
Category :
Languages : en
Pages : 282
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Book Description
RNA Polymerase (Pol) II transcribes protein-coding genes in eukaryotic cells. Transcription by Pol II is coordinated with processes through the carboxyl-terminal domain (CTD) of its largest subunit, Rpb1. Cyclin-dependent kinases (CDKs) phosphorylate CTD heptad repeats to influence their binding properties and thereby govern co-transcriptional mRNA processing. Transcription factor (TF) IIH-associated Cdk7 phosphorylates Ser5 residues to recruit capping enzymes, while Cdk9 promotes elongation by phosphorylating the CTD and the processivity factor Spt5. I examined the functions of these essential kinases in fission yeast in a putative mRNA quality control mechanism that could ensure that only fully capped transcripts are elongated. I found that Cdk9 forms a constitutive and stable complex with the cyclin Pch1 and the 5'-cap methyltransferase Pcm1 in vivo. Using chemical genetics, we showed that Mcs6 activity is required to recruit the Cdk9-Pch1-Pcm1 complex to a subset of CDK-dependent genes. In vitro, I showed that phosphorylation of the CTD by Mcs6 stimulates subsequent phosphorylation by Cdk9. Together, these observations support a model in which Mcs6 and Cdk9 act sequentially to coordinate elongation and capping of select pre-mRNAs. To test that model, I undertook a functional dissection of the fission yeast Cdk9-Pch1-Pcm1 complex. I show that a Cdk9 carboxyl-terminal extension, distinct from the catalytic domain, mediates binding to Pcm1 and the Pol II CTD. Removal of this segment leads to growth defects and transcriptional deficiencies. These phenotypes are suppressed by Pcm1 overproduction, suggesting that normal transcript elongation and gene expression depend on physical linkage between Cdk9 and Pcm1. The extension is dispensable, however, for recognition by Cdk9 of CTD substrates "primed" by Mcs6. Cdk9 prefers CTD peptides phosphorylated at Ser7 over unmodified repeats. In vivo, Ser7 phosphorylation depends on Mcs6 activity, suggesting a mechanism to order transcriptional CDK functions, independent of chromatin recruitment. Therefore, fission yeast Cdk9 comprises a catalytic domain sufficient for primed substrate recognition, and a multivalent recruitment module that couples transcription with capping. Together, these results support a proposed model whereby CTD phosphorylation by Mcs6 stimulates subsequent Cdk9 activity and the Cdk9/Pcm1 complex serves to coordinate capping with transcript elongation, thereby protecting mRNA quality.
Author:
Publisher:
ISBN: 9780815332183
Category : Cells
Languages : en
Pages : 0
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Book Description
Author: Nancy Y. Ip
Publisher: Springer Science & Business Media
ISBN: 0387788875
Category : Medical
Languages : en
Pages : 326
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Book Description
Cyclin Dependent Kinase 5 provides a comprehensive and up-to-date collection of reviews on the discovery, signaling mechanisms and functions of Cdk5, as well as the potential implication of Cdk5 in the treatment of neurodegenerative diseases. Since the identification of this unique member of the Cdk family, Cdk5 has emerged as one of the most important signal transduction mediators in the development, maintenance and fine-tuning of neuronal functions and networking. Further studies have revealed that Cdk5 is also associated with the regulation of neuronal survival during both developmental stages and in neurodegenerative diseases. These observations indicate that precise control of Cdk5 is essential for the regulation of neuronal survival. The pivotal role Cdk5 appears to play in both the regulation of neuronal survival and synaptic functions thus raises the interesting possibility that Cdk5 inhibitors may serve as therapeutic treatment for a number of neurodegenerative diseases.
Author: Stefan Hohmann
Publisher: Springer Science & Business Media
ISBN: 3540456112
Category : Science
Languages : en
Pages : 398
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Book Description
Every cell has developed mechanisms to respond to changes in its environment and to adapt its growth and metabolism to unfavorable conditions. The unicellular eukaryote yeast has long proven as a particularly useful model system for the analysis of cellular stress responses, and the completion of the yeast genome sequence has only added to its power This volume comprehensively reviews both the basic features of the yeast genral stress response and the specific adapations to different stress types (nutrient depletion, osmotic and heat shock as well as salt and oxidative stress). It includes the latest findings in the field and discusses the implications for the analysis of stress response mechanisms in higher eukaryotes as well.
Author: Gordon Carmichael
Publisher: Springer Science & Business Media
ISBN: 1592599354
Category : Science
Languages : en
Pages : 343
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Book Description
A collection of readily reproducible methods for the design, preparation, and use of RNAs for silencing gene expression in cells and organisms. The techniques range widely and include methods addressing the biochemical aspects of the silencing machinery, RNA silencing in non-mammalian organisms, and the in vivo delivery of siRNAs and silencing vectors. There are also techniques for designing, preparing, and using RNAs to silence gene expression, for fine-tuning regulation by targeting specific isoforms of a given gene, and for the study and use of microRNAs. The protocols follow the successful Methods in Molecular BiologyTM series format, each offering step-by-step laboratory instructions, an introduction outlining the principle behind the technique, lists of the necessary equipment and reagents, and tips on troubleshooting and avoiding known pitfalls.
Author:
Publisher:
ISBN:
Category : Medicine
Languages : en
Pages : 1972
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Book Description
Vols. for 1963- include as pt. 2 of the Jan. issue: Medical subject headings.
Author: Peter A. Hall
Publisher: John Wiley & Sons
ISBN: 9780470779699
Category : Science
Languages : en
Pages : 380
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Book Description
"The authors represent most of the key figures and the work and the book as a whole is an essential reference for the newcomer or specialist in this area and for any student of eukaryotic cell structure and function. This is an important and wonderful reference." –Microbiology Today, May 2009 Septins are an evolutionarily conserved group of GTP-binding and filament-forming proteins that were originally discovered in yeast. Once the preserve of a small band of yeast biologists, the field has grown rapidly in the past few years and now encompasses the whole of animal and fungal biology. Furthermore, septins are nowadays recognized to be involved in a variety of disease processes from neoplasia to neurodegenerative conditions. This book comprehensively examines the septin gene family and their proteins, providing those new to this research area with a detailed and wide ranging introduction to septin biology. It starts with a unique historical perspective on the development of the field, from its beginnings in the screen for cell division mutants by the Nobel Laureate Lee Hartwell. The evolution of the septin gene family then forms a basis for consideration of the biochemistry and functions of septins in yeast and other model organisms including C. elegans and Drosophila. A major part of the book considers the diversity of septins in mammals, their functions and properties as well as their involvement in normal and abnormal cellular states, followed by a speculative overview from the editors of the key questions in septin research and of where the field may be headed. In addition, several appendices summarise important information for those in, or just entering, the field, e.g. nomenclature and septin and septin-like sequences. This book is an essential source of reference material for researchers in septin biology, cell biology, genetics and medicine, in particular pathology, including areas of neurobiology, oncology, infectious disease and developmental biology.
Author: Khalil Ahmed
Publisher: Springer Science & Business Media
ISBN: 9780792376668
Category : Science
Languages : en
Pages : 200
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Book Description
Signal Transduction through phosphorylation and dephosphorylation of proteins in the cell is now a well-recognized mechanism involved in countless physiological and pathological processes. Consequently, the enzymes, known as protein kinases, which catalyze the phosphorylation of proteins, are critical regulators of cellular events. One of these protein kinases is the protein kinase CK2 (also known as casein kinase 2) that has been implicated in multiple functions including control of cell growth and proliferation. CK2 is a protein serine/threonine kinase which is a highly conserved and ubiquitous protein kinase. It is localized in the cytoplasmic and nuclear compartments, which accords with its multiple functional activities in the cell. Pertinent to this is also the recognition that a large number of putative substrates for this kinase have been identified in various compartments of the cell. New evidence from several laboratories has further reinforced the involvement of CK2 in signal transduction related to many cellular functions, thus underscoring the significance of its functional role in normal and abnormal cell growth and proliferation. This volume provides an overview of the state of knowledge concerning this intriguing protein kinase. It brings together contributions from leading investigators engaged in research in this field. Key developments during the past three years pertain to the elaboration of the crystal structure and definition of novel functions of the kinase, such as its role as an inhibitor of apoptosis. Additionally, the shuttling of the kinase to various compartments in response to physiological and stress stimuli appears to be a key feature of the functional regulation of its activity in the cell.
Author:
Publisher:
ISBN:
Category : Cells
Languages : en
Pages : 652
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Book Description
Author: Cai Huang
Publisher: BoD – Books on Demand
ISBN: 9535107372
Category : Medical
Languages : en
Pages : 482
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Book Description
15 chapters on protein phosphorylation and human health written by expert scientists. Covers most important research hot points, such as Akt, AMPK and mTOR. Bridges the basic protein phosphorylation pathways with human health and diseases. Detailed and comprehensive text with excellent figure illustration.
