Physiological Role and Quantitative Aspects of Human Nonsense-mediated MRNA Decay (NMD) PDF Download
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Author: Marcelo Viegas
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Author: Marcelo Viegas
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Author: Samantha Jones
Publisher:
ISBN:
Category :
Languages : en
Pages : 148
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The nonsense-mediated RNA decay (NMD) pathway serves as a quality control mechanism and regulator of normal gene expression. Here, we report our analysis of two gene paralogs, UPF3A and UPF3B, which we found to have opposing roles in NMD. Previous gain-of-function studies indicated that UPF3A encodes a protein exhibiting little or no NMD activity. We were therefore perplexed as to what property allowed UPF3A to survive since it arose at the dawn of vertebrates, over 400 million years ago. Using loss-of-function approaches, we found that UPF3A is a potent NMD repressor both in vitro and in vivo. We generated Upf3a-null mice and found that global UPF3A knockout causes mouse embryonic lethality and conditional knockout in male germ cells leads to spermatogenic defects, particularly at the meiotic stage where UPF3A is highly expressed. We propose that UPF3A serves as a molecular rheostat to upregulate critical NMD target mRNAs at specific developmental time points, a model supported by RNAseq analysis. In contrast to UPF3A, UPF3B does not function in the testis; instead it is critical for neural development and human cognition. Mutations in UPF3B cause a form of X-linked intellectual disability, with patients often also suffering from autism or schizophrenia. To understand UPF3B function in vivo, we generated Upf3b-null mice and found that they display defects in fear-conditioned learning and pre-pulse inhibition (PPI), a measure of sensorimotor inhibition often deficient in individuals with schizophrenia. Consistent with these defects, cortical pyramidal neurons from Upf3b-null mice exhibit decreased spine density and RNAseq analysis identified transcripts encoding key neural regulators as targets of UPF3B. Our findings demonstrated that UPF3A and UPF3B have opposing functions in the NMD pathway and act in distinct developmental processes. A major focus of my thesis work was to further investigate the role of UPF3B in neurogenesis using the olfactory system as a model. We and found (at the transcript level) fewer early OE cell types in the Upf3b-null mouse but similar numbers of mOSNs, the cells responsible for odorant detection. Pooled RNA sequencing of Upf3b-null and wild type mOSNs revealed decreased class-II olfactory receptor (olfr) expression, which may (at least partially) underlie a previously observed partial olfaction defect. When comparing pooled data with our single cell RNA sequencing (scRNAseq) results, we also found a significantly reduced number of cells expressing one or more olfrs. Closer examination of the scRNAseq data also indicated a role for UPF3B in immune response and presented the possibility that multiple OE cell types are bifunctional, playing a role in both detecting odorant molecules and responding to infection. This work was also the first to define the "translome" of pooled mOSNs, building a framework for what transcripts are more often translated in a healthy model and how that can change in a disease (in our case UPF3B-depleted) state.
Author: Eleen Yee Lam Shum
Publisher:
ISBN: 9781321649246
Category :
Languages : en
Pages : 238
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Nonsense-mediated RNA Decay (NMD) is a post-transcriptional pathway that degrades aberrant mRNAs, as well as up to ~5% of normal mRNAs. NMD is orchestrated by various factors, including the Upframeshift (UPF) proteins that recognize mRNAs with NMD-inducing features. Of all known factors that participate in NMD, UPF3 is unique in being encoded by two gene paralogs - UPF3A and UPF3B. Loss of UPF3B in humans causes intellectual disability and other neurological disorders. In these patients, as well as other settings in which UPF3B is absent, UPF3A is dramatically upregulated, suggesting that UPF3A compensates for UPF3B. To date, the relationship between these two sister genes and their physiological importance remain elusive.For my dissertation, I elected to study the role of both UPF3A and UPF3B using knockout mouse models. In Upf3b-KO mice, I studied the effect of UPF3B in neuronal development in both the brain and the olfactory epithelium, as well as its downstream effectors in these tissues. I also generated an Upf3a knockout mouse model to study the role of UPF3A in vivo. In the course of my studies, I found that UPF3A, unlike UPF3B, is required for embryonic development. I also discovered that UPF3A is important for spermatogenesis, consistent with the fact that this protein is more highly expressed in the testis than any other adult tissues. Surprisingly, I discovered that while the UPF3A gene is closely related with the UPF3B gene, these two genes have opposing functions. UPF3B promotes NMD, while UPF3A is a NMD inhibitor in several different contexts. Since these two UPF3 proteins are expressed at unequal levels in various tissues, my results suggest that the ratio of these two paralogs dictate the tissue-specific strength of NMD. Together, my research has provided one of the first examples of gene paralogs that have evolved an antagonistic relationship and it has shed light on a unique system to regulate gene expression in a tissue specific and developmentally regulated manner.
Author: Lynne E. Maquat
Publisher: Academic Press
ISBN: 9780123745842
Category : Science
Languages : en
Pages : 464
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Book Description
Specific complexes of protein and RNA carry out many essential biological functions, including RNA processing, RNA turnover, and RNA folding, as well as the translation of genetic information from mRNA into protein sequences. Messenger RNA (mRNA) decay is now emerging as an important control point and a major contributor to gene expression. Continuing identification of the protein factors and cofactors and mRNA instability elements responsible for mRNA decay allow researchers to build a comprehensive picture of the highly orchestrated processes involved in mRNA decay and its regulation. * Covers the nonsense-mediated mRNA decay (NMD) or mRNA surveillance pathway * Expert researchers introduce the most advanced technologies and techniques * Offers step-by-step lab instructions, including necessary equipment and reagents
Author: Fabrice Lejeune
Publisher: Academic Press
ISBN: 0128044691
Category : Science
Languages : en
Pages : 192
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Book Description
Nonsense Mutation Correction in Human Diseases: An Approach for Targeted Medicine provides an introduction on genetic diseases, discusses the prevalence of nonsense mutations, the consequences of a nonsense mutation for the expression of the mutant gene, and the presentation of the nonsense-mediated mRNA decay (NMD). It presents the mechanism of action and rationale associated with each strategy to correct nonsense mutations with the results of clinical trials to further support this basis. In addition, the book shows how it may be possible to combine several of these strategies to ultimately improve the efficiency of correction, also suggesting the future goals and objectives to improve treatment modalities in this evolving sphere of personalized medicine. - Features basic biological and clinical constructs that inform the application of genomic data to clinical decision-making - Includes theories and methods that can be used to link bio-molecular and clinical phenotypes so as to enable integrative hypothesis discovery, testing, and downstream evidence-based practice - Provides design patterns and use cases that contextualize the clinical decision-making and evidence-based practice relative to real world requirements and stakeholders
Author:
Publisher: Academic Press
ISBN: 0128024887
Category : Science
Languages : en
Pages : 412
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Book Description
Methods in Enzymology: Visualizing RNA Dynamics in the Cell continues the legacy of this premier serial with quality chapters authored by leaders in the field. This volume covers research methods visualizing RNA dynamics in the cell, and includes sections on such topics as identification of RNA cis-regulatory sequences, IRAS, IMAGEtags, MERFISH, plant RNA labeling using MS2, and visualization of 5S dynamics in live cells using photostable corn probe. - Continues the legacy of this premier serial with quality chapters authored by leaders in the field - Covers research methods in visualizing RNA dynamics in the cell - Contains sections on such topics as identification of RNA cis-regulatory sequences, IRAS, IMAGEtags, MERFISH, plant RNA labeling using MS2 and visualization of 5S dynamics in live cells using photostable corn probe
Author: Stefano Crespi
Publisher: Royal Society of Chemistry
ISBN: 183916526X
Category : Science
Languages : en
Pages : 507
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Providing critical analysis of emerging and well-established topics, this book is essential reading for anyone wanting to keep up to date with the literature on photochemistry and its applications. Volume 49 combines reviews on the latest advances in photochemical research with specific highlights in the field. The first section includes periodical reports of the recent literature on physical and inorganic aspects, including reviews of the molecules employed as dyes in art, light induced reactions in cryogenic matrices, photobiological systems studied by time-resolved infrared spectroscopy and photophysics, and photochemistry of transition metal complexes. This selection is completed by reviews of the literature on solar photocatalysis for water decontamination and disinfection and for water splitting/hydrogen production. Coverage continues in the second part with highlighted topics, from the use of aromatic carbonyls as photocatalysts and photoinitiators in synthesis, photoinduced and photocatalysed decarboxylation reactions, development of dye-sensitized solar cells, design of luminescent water-soluble systems, and applications of plasmonic nanoparticles. This volume also includes a third section entitled ‘SPR Lectures on Photochemistry’, where leading scientists in photochemistry provide examples to introduce a photochemical topic to academic readers, offering precious assistance to students in this field.
Author: Nozomu Mori
Publisher: Springer
ISBN: 4431557636
Category : Medical
Languages : en
Pages : 435
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Book Description
This book brings together the most up-to-date information on recent research results of leading laboratories on aging science in East Asia, particularly in Japan, Korea, and Hong Kong. Starting with a comprehensive overview of various hypotheses on biological mechanisms of aging by Dr. Sataro Goto, each chapter covers broad aspects of the most recent findings in aging-related topics: centenarian studies and genome analysis of progeria, metabolic biochemistry and neurobiology, longevity controls in yeast and nematodes, oxidative stress and calorie restriction, and neurodegeneration mechanisms in Alzheimer’s and Huntington’s diseases, with further potential therapeutic approaches to these age-related neurodegenerative diseases. Also included, in part, is a summary and the outcomes of a scientific discussion forum called the Asian Aging Core for Longevity (AACL) that has been held annually alternating between Japan and Korea during the last decade. This book can serve as a useful resource for finding appropriate collaborators in the areas it covers. The target readership is made up of graduate students and researchers at universities, medical and/or life-science schools, and biomedical and pharmaceutical institutes. Why does aging exist? How do we age? How is each organism’s lifespan determined? These are fundamental questions in the field. We may be still far from achieving a complete view of aging mechanisms, but this book, Aging Mechanisms, offers an excellent opportunity to become familiar with the most updated progress in the biomedical research of aging in Japan and Korea, the two leading nations for human longevity.
Author: Rosanna Asselta
Publisher: Frontiers Media SA
ISBN: 2889662357
Category : Science
Languages : en
Pages : 197
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Book Description
This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact.
Author: Richard Ellis Ford Matthews
Publisher: Gulf Professional Publishing
ISBN: 9780123611604
Category : Plant diseases
Languages : en
Pages : 1084
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Book Description
It has been ten years since the publication of the third edition of this seminal text on plant virology, during which there has been an explosion of conceptual and factual advances. The fourth edition updates and revises many details of the previous editon, while retaining the important older results that constitute the field's conceptual foundation. Key features of the fourth edition include: * Thumbnail sketches of each genera and family groups * Genome maps of all genera for which they are known * Genetic engineered resistance strategies for virus disease control * Latest understanding of virus interactions with plants, including gene silencing * Interactions between viruses and insect, fungal, and nematode vectors * New plate section containing over 50 full-color illustrations.
