Isolation and Characterization of Hupf1 Containing Protein Complexes and Their Role in Nonsense Mediated MRNA Decay PDF Download
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Author: Thomas Schell
Publisher:
ISBN:
Category :
Languages : en
Pages : 256
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Book Description
Author: Thomas Schell
Publisher:
ISBN:
Category :
Languages : en
Pages : 256
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Book Description
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages :
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MRNAs containing premature translation termination codons (PTCs) are usually degraded by the nonsense-mediated mRNA decay (NMD) pathway. The mechanism of NMD in mammals is largely unknown. The cytoplasmic protein Hupf1 was the only trans-acting factor of NMD in mammals that was known at the beginning of this study. In order to identify and characterize proteins that are required for NMD in mammals, Hupf1-containing protein complexes were affinity purified from HeLa cells that stably express recombinant, double affinity tagged Hupf1-2tag at physiological levels. The analysis of these purified complexes by mass spectrometry revealed the presence of the proteins Hupf2 and Poly(A)-binding protein 1 (Pabp1). Using size exclusion chromatography it was shown that the majority of Hupf1 occurs as a monomer, but two complexes of distinct composition could be isolated. Further analysis of affinity purified Hupf1-containing complexes by Western Blot revealed that the presence of intact RNA stabilizes the interaction of Hupf1 with Hupf2 as well as the interaction of Hupf1 with the recently identified NMD factors Hupf3a and Hupf3b. The interaction between Pabp1 and Hupf1 was demonstrated to be strictly RNA-dependent. Even though the components of the exon-exon-junction complex (EJC) or the translational release factor eRF3 have been implicated in NMD in mammals, these proteins could not be found in the purified Hupf1-containing complexes, indicating that these proteins interact with Hupf1 transiently or not at all. The results described in this thesis indicate that Hupf1 occurs in different stable protein complexes and that Hupf2 and Pabp1 are novel interaction partners of Hupf1 and might be involved in NMD in mammals. RNA was found to play an important role for the stability of the interactions of Hupf1 with other proteins. The dynamic interactions of Hupf1 are likely to play an important role for the recognition of PTC-containing mRNAs and their subsequent destabilization.
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Category :
Languages : en
Pages : 172
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Author: Kuchma Sherry Lynn
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Category :
Languages : en
Pages : 164
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Category : Medicine
Languages : en
Pages : 1912
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Category : Cytology
Languages : en
Pages : 502
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Category : Dissertations, Academic
Languages : en
Pages : 1044
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Author: Rita Sattler
Publisher: Springer
ISBN: 331989689X
Category : Medical
Languages : en
Pages : 321
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It has become evident over the last years that abnormalities in RNA processing play a fundamental part in the pathogenesis of neurodegenerative diseases. Cellular viability depends on proper regulation of RNA metabolism and subsequent protein synthesis, which requires the interplay of many processes including transcription, pre--‐mRNA splicing, mRNA editing as well as mRNA stability, transport and translation. Dysfunction in any of these processes, often caused by mutations in the coding and non--‐ coding RNAs, can be very destructive to the cellular environment and consequently impair neural viability. The result of this RNA toxicity can lead to a toxic gain of function or a loss of function, depending on the nature of the mutation. For example, in repeat expansion disorders, such as the newly discovered hexanucleotide repeat expansion in theC9orf72 gene found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a toxic gain of function leads to the formation of RNA foci and the sequestration of RNA binding proteins (RBPs). This in return leads to a loss of function of those RBPs, which is hypothesized to play a significant part in the disease progression of ALS and FTD. Other toxicities arising from repeat expansions are the formation of RNA foci, bi--‐directional transcription and production of repeat associated non--‐ATG (RAN) translation products. This book will touch upon most of these disease mechanisms triggered by aberrant RNA metabolism and will therefore provide a broad perspective of the role of RNA processing and its dysfunction in a variety of neurodegenerative disorders, including ALS, FTD, Alzheimer’s disease, Huntington’s disease, spinal muscular atrophy, myotonic dystrophy and ataxias. The proposed authors are leading scientists in the field and are expected to not only discuss their own work, but to be inclusive of historic as well as late breaking discoveries. The compiled chapters will therefore provide a unique collection of novel studies and hypotheses aimed to describe the consequences of altered RNA processing events and its newest molecular players and pathways.
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Category : Genetics
Languages : en
Pages : 780
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Author: Angus I. Lamond
Publisher: Springer
ISBN: 9783662223277
Category : Science
Languages : en
Pages : 221
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Book Description
he past fifteen years have seen tremendous growth in our understanding of T the many post-transcriptional processing steps involved in producing func tional eukaryotic mRNA from primary gene transcripts (pre-mRNA). New processing reactions, such as splicing and RNA editing, have been discovered and detailed biochemical and genetic studies continue to yield important new insights into the reaction mechanisms and molecular interactions involved. It is now apparent that regulation of RNA processing plays a significant role in the control of gene expression and development. An increased understanding of RNA processing mechanisms has also proved to be of considerable clinical importance in the pathology of inherited disease and viral infection. This volume seeks to review the rapid progress being made in the study of how mRNA precursors are processed into mRNA and to convey the broad scope of the RNA field and its relevance to other areas of cell biology and medicine. Since one of the major themes of RNA processing is the recognition of specific RNA sequences and structures by protein factors, we begin with reviews of RNA-protein interactions. In chapter 1 David Lilley presents an overview of RNA structure and illustrates how the structural features of RNA molecules are exploited for specific recognition by protein, while in chapter 2 Maurice Swanson discusses the structure and function of the large family of hnRNP proteins that bind to pre-mRNA. The next four chapters focus on pre-mRNA splicing.
