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The regulation of mRNA translation and degradation is essential for proper gene expression. In eukaryotes, a major mRNA degradation pathway is initiated by deadenylation, followed by decapping, and ultimately 5'-3' exonucleolytic digestion. Removal of the mRNA 5' cap is an irreversible step in mRNA degradation, and is postulated to require dissociation of the mRNA from the ribosomes and packaging into sub-cellular, ribosome-free granules termed P-bodies. Based on this and other observations, a "two-step" model of eukaryotic mRNA degradation had been proposed that mRNA translation and degradation occur in different compartments within the cell. Recent findings suggest, however, that mRNA degradation may occur independent of P-bodies. Consequently, an important but unresolved issue in the field is to determine the context in which mRNA is degraded. In my study, I have demonstrated that the three steps of mRNA decay, deadenylation, decapping, and 5'-3' exonucleolytic digestion, occur co-translationally. Specifically, mRNA deadenylation does not lead to ribosome dissociation. Second, I found that decapped mRNA mainly bound to polyribosomes, suggesting that decapping occurs during translation. In addition, using kinetic analysis, I demonstrated that mRNA decapping is initiated while the mRNA is on polyribosomes. Third, I observed that in wild-type cells, exonucleolytic decay fragments are polyribosome associated when ribosome transit is slowed in cis. Lastly, using an innovative assay I designed, I detected decapping products from endogenous mRNAs mainly on polyribosomes in wild type cells. These results clearly demonstrate that under normal physiological conditions, mRNA degradation occurs while the mRNA is still associated with ribosomes. In addition to the normal mRNA turnover pathway, I observed that mRNA decapping triggered by nonsense-mediated mRNA decay, an important mRNA quality control mechanism, also occurs on polyribosomes. Collectively, these results indicate that polyribosomes are the major sites for destroying both normal and aberrant mRNAs within eukaryotic cells
"The regulation of eukaryotic gene expression is a highly coordinated, multi-layered program that dictates cellular function. A fundamental aspect of this program encompasses processes that regulate protein synthesis after a messenger RNA (mRNA) is transcribed from its DNA template and is referred to as post-transcriptional control. Specifically, mRNAs can be regulated at the level of stability, translational efficiency and cellular localization. Almost all eukaryotic mRNAs possess a 5’ cap and a 3’ polyadenylated (poly(A)) tail, and these structural elements have broad implications in mRNA control. The presence of the 5’ cap and 3’ poly(A) tail act to enhance mRNA translation and protect the mRNA from degradation by exonucleases. Intuitively, regulatory mechanisms that act on the 5’ cap and 3’ poly(A) exist to inhibit translation and permit mRNA degradation. The major process by which mRNAs are degraded involves the sequential removal of the 3’ poly(A) tail and 5’ cap, followed by nucleolysis by the 5’-3’ exoribonuclease XRN1. Specifically, mRNA decapping is catalyzed by the DCP1-DCP2 decapping complex and its efficiency depends on a multitude of decapping enhancers including LSM14, 4E-T, DDX6, PATL1, EDC3 and EDC4. LSM14 is recognized to play a role in mRNA decapping and translational repression, however, how it interacts with mRNA decay factors has remained fragmentary. Herein, we provide important biochemical and structural insight into how LSM14 interacts with 4E-T and DDX6. We establish that the LSM14-4E-T interaction is necessary and sufficient for the LSM14 LSM domain to translationally repress tethered reporter mRNAs. LSM14, PATL1, EDC3 and 4E-T bind DDX6 in a mutually exclusive manner. However, we uncover that LSM14 interfaces DDX6 in a unique anti-parallel fashion in contrast to other decapping factors, in part to present the highly conserved FFD motif of LSM14 as a novel recruitment platform for the decapping activator EDC4. Finally, we ascertain that the interactions that LSM14 maintains with 4E-T, DDX6 and EDC4 are required for higher order assembly and P-body maintenance.Although the removal of the 3’ poly(A) tail is the initial step during the major mRNA degradation pathway, it can be bypassed by certain modes of mRNA turnover that remain less well understood. Herein we provide convincing evidence for a deadenylation-independent mechanism of mRNA decay mediated by MARF1. We establish that MARF1 interacts with the decapping machineries but does not interface the deadenylation complex. We further determine that MARF1 leads to the degradation of tethered reporter mRNAs by a mechanism that does not necessitate mRNA deadenylation nor its ability to associate with the decapping machineries. Instead MARF1 requires its NYN nuclease domain to mediate mRNA decay and we reveal that the crystal structure of this domain adopts a PIN-like fold with significant structural similarity to the endoribonuclease domains of MCPIP1 and SMG6. We ascertain that the MARF1 NYN domain exhibits endoribonuclease activity in vitro, hence unveiling its ability to function in a deadenylation-independent manner.The culmination of original findings presented in my thesis unravels the complex protein interaction network for human mRNA degradation. Our data positions LSM14 at the center of this network and reveals how it couples mRNA deadenylation and decapping. Moreover, we identify a novel pathway of mRNA decay mediated by MARF1 and show that it functions as an endoribonuclease in a deadenylation-independent manner. These data provide valuable insights into mechanisms of mRNA degradation that will have far reaching implications for understanding the control of gene expression and its deregulation in clinical pathologies"--
Since the 1996 publication of Translational Control, there has been fresh interest in protein synthesis and recognition of the key role of translation control mechanisms in regulating gene expression. This new monograph updates and expands the scope of the earlier book but it also takes a fresh look at the field. In a new format, the first eight chapters provide broad overviews, while each of the additional twenty-eight has a focus on a research topic of more specific interest. The result is a thoroughly up-to-date account of initiation, elongation, and termination of translation, control mechanisms in development in response to extracellular stimuli, and the effects on the translation machinery of virus infection and disease. This book is essential reading for students entering the field and an invaluable resource for investigators of gene expression and its control.
Dysfunction of nuclear-cytoplasmic transport systems has been associated with many human diseases. Thus, understanding of how functional this transport system maintains, or through dysfunction fails to maintain remains the core question in cell biology. In eukaryotic cells, the nuclear envelope (NE) separates the genetic transcription in the nucleus from the translational machinery in the cytoplasm. Thousands of nuclear pore complexes (NPCs) embedded on the NE selectively mediate the bidirectional trafficking of macromolecules such as RNAs and proteins between these two cellular compartments. In this book, the authors integrate recent progress on the structure of NPC and the mechanism of nuclear-cytoplasmic transport system in vitro and in vivo.
This is the first comprehensive review of mRNA stability and its implications for regulation of gene expression. Written by experts in the field, Control of Messenger RNA Stability serves both as a reference for specialists in regulation of mRNA stability and as a general introduction for a broader community of scientists. Provides perspectives from both prokaryotic and eukaryotic systems Offers a timely, comprehensive review of mRNA degradation, its regulation, and its significance in the control of gene expression Discusses the mechanisms, RNA structural determinants, and cellular factors that control mRNA degradation Evaluates experimental procedures for studying mRNA degradation
A Top 25 CHOICE 2016 Title, and recipient of the CHOICE Outstanding Academic Title (OAT) Award. How much energy is released in ATP hydrolysis? How many mRNAs are in a cell? How genetically similar are two random people? What is faster, transcription or translation?Cell Biology by the Numbers explores these questions and dozens of others provid
The NMDA receptor plays a critical role in the development of the central nervous system and in adult neuroplasticity, learning, and memory. Therefore, it is not surprising that this receptor has been widely studied. However, despite the importance of rhythms for the sustenance of life, this aspect of NMDAR function remains poorly studied. Written
There is now compelling evidence that the complexity of higher organisms correlates with the relative amount of non-coding RNA rather than the number of protein-coding genes. Previously dismissed as “junk DNA”, it is the non-coding regions of the genome that are responsible for regulation, facilitating complex temporal and spatial gene expression through the combinatorial effect of numerous mechanisms and interactions working together to fine-tune gene expression. The major regions involved in regulation of a particular gene are the 5’ and 3’ untranslated regions and introns. In addition, pervasive transcription of complex genomes produces a variety of non-coding transcripts that interact with these regions and contribute to regulation. This book discusses recent insights into the regulatory roles of the untranslated gene regions and non-coding RNAs in the control of complex gene expression, as well as the implications of this in terms of organism complexity and evolution.​
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.