The Biology of mRNA: Structure and Function (Advances in Experimental Medicine and Biology Book 1203)

"The book provides an overview on the different aspects of gene regulation from an mRNA centric viewpoint, including how mRNA is assembled and self-assembles in a complex consisting of RNA and proteins, and how its ability to be translated at the right time and space depends on many processes acting on the mRNAs, leading to a properly folded complex. This book shows how new technologies have led to a better understanding of these processes and their connected diseases. The book is written for scientists in fundamental and applied biomedical research working on different aspects of gene regulation. It is also targeted to an audience that is not implicated in these fields directly, but wants to gain a better understanding of mRNA biology"--Page [4] of cover Preface 6 Contents 8 Chapter 1: Mechanism and Regulation of Co-transcriptional mRNP Assembly and Nuclear mRNA Export 10 1.1 Introduction 10 1.2 Co-transcriptional mRNP Assembly 13 1.2.1 Cap-Binding Complex 15 1.2.2 The TREX Complex 15 1.2.3 Tho1 and CIP29 17 1.2.4 Npl3, Nab2, and Mammalian SR-Proteins 17 1.2.5 THSC Complex 18 1.2.6 The mRNA Exporter Mex67-Mtr2 19 1.2.7 General Aspects of mRNP Assembly 19 1.3 RNA Helicases Involved in mRNP Assembly 20 1.3.1 Dbp2/p68 (DDX5) 21 1.3.2 Yeast Sub2/Human UAP56 (DDX39B) 21 1.3.3 Yeast Dbp5/Human DBP5 (DDX19B) 22 1.4 mRNP Assembly and mRNA Export Under Stress 23 1.5 Misregulation of mRNP Assembly Is Linked to Diseases 25 1.5.1 Genome Instability and Cancer 25 1.5.2 Misregulation of mRNP Assembly Linked to Neurodevelopmental Disorders 27 1.5.3 Nuclear mRNP Export Highjacked by Viruses 28 1.6 Perspectives 29 References 30 Chapter 2: It ́s Not the Destination, It ́s the Journey: Heterogeneity in mRNA Export Mechanisms 41 2.1 Introduction 42 2.2 The Ground State: Bulk Export Pathways for mRNAs 43 2.3 Orthology of Bulk mRNA Export Factors 48 2.3.1 mRNA Export Adaptor Heterogeneity 48 2.3.1.1 UIF 50 2.3.1.2 Luzp4 50 2.3.1.3 Other Candidate Export Adaptors: SKAR and ZC11A 51 2.3.2 Export Coadaptor Heterogeneity 51 2.3.2.1 ChTOP 52 2.3.2.2 RBM15 and RBM15B 52 2.3.3 Additional Heterogeneity Within the TREX Complex: UAP56 and URH49 53 2.3.4 The NXF1 Family of Export Receptors 54 2.3.5 Chaperoning of NXF1:NXT1 to the NPC: Pervasive Mechanism or ``Fast-Track ́ ́ Selectivity? 55 2.3.6 Defining the Complete Suite of Bulk mRNA Export Orthologs and Parallel Pathways 55 2.4 Noncanonical Recruitment of NXF1 to mRNA: USER Codes and mRNA Regulons 57 2.4.1 USER Codes in the Export of Intronless mRNAs 58 2.4.1.1 The SRSF Family of Splicing Factors 58 2.4.1.2 The Prp19 Complex, U2AF, and the CAR-E Element 60 2.4.2 The Signal Sequence Coding Region as a Dual-Functional Regulatory Element 60 2.4.3 Posttranscriptional Control of USER Code Recognition by Aly/REF 61 2.4.4 Trans-Acting Factors Without a USER Code: Candidate mRNA Regulon Export Factors 62 2.4.5 The AU-Rich Element as a mRNA Export USER Code 63 2.5 Posttranslational Formation of USER Codes by mRNA Modification 64 2.5.1 N6-Methyladenosine in the Regulation of mRNA Export 65 2.5.2 N5-Methylcytosine as a Possible Regulator of Aly/REF-Dependent Recruitment to mRNA 66 2.6 Regulation of mRNA Export by the Protein Export Receptor CRM1 67 2.6.1 A Nuclear Role for the Cytoplasmic Cap-Binding Protein eIF4E 68 2.6.2 Teaching an Old Dog New Tricks: CRM1-Dependent Export Via NXF3 70 2.6.3 CRM1 Versus NXF1 in the Export of mRNAs in Metazoans 71 2.7 Roles for the NPC in mRNA Export Heterogeneity 71 2.7.1 NUP96 in Cell Cycle and Interferon Regulation 72 2.7.2 Bypassing the NPC: Nuclear Membrane Budding for the Export of Large mRNP Complexes 73 2.8 Outstanding Questions in mRNA Export Heterogeneity 74 2.8.1 Stoichiometry of Export Adaptors/Coadaptors on mRNA 74 2.8.2 Posttranslational Regulation of mRNA Export Pathways in Response to Cellular Stimuli 76 2.8.3 Cooperation or Competition of Export Pathways on Common mRNAs 77 2.9 Concluding Remarks 78 References 78 Chapter 3: View from an mRNP: The Roles of SR Proteins in Assembly, Maturation and Turnover 90 3.1 General Introduction 90 3.2 The Family of Classical SR Proteins 92 3.3 Regulation of SR Protein Activity 94 3.4 SR Protein Recruitment to Pre-mRNAs 97 3.5 Co-transcriptional Splicing 100 3.6 Regulation of Splicing 103 3.7 mRNP Maturation and Remodelling 105 3.8 3′End Processing and Alternative Polyadenylation 106 3.9 mRNP Export and Nucleo-Cytoplasmic Shuttling 106 3.10 Nonsense-Mediated Decay 108 3.11 mRNP Translation 109 3.12 mRNP Remodelling and Re-import of SR Proteins 110 3.13 Concluding Remarks 110 References 111 Chapter 4: The Nuclear RNA Exosome and Its Cofactors 120 4.1 The RNA Exosome 120 4.1.1 The Core 120 4.1.2 Catalytic Subunits 121 4.1.3 Lrp1 and Mpp6 122 4.2 RNA Helicase Activities Central to Exosome Function: Mtr4/Ski2 123 4.3 S. cerevisiae 123 4.3.1 The TRAMP and NNS Complexes 123 4.3.2 Nucleolar Exosome Cofactors 125 4.4 S. pombe 126 4.4.1 TRAMP 126 4.4.2 MTREC 126 4.5 Human 129 4.5.1 TRAMP 129 4.5.2 NEXT 130 4.5.3 PAXT 131 4.5.4 The Nuclear RNA Cap-Binding Complex 132 4.6 Nuclear Decay vs. RNA Export 132 4.7 Concluding Remarks 133 References 134 Chapter 5: 3′-UTRs and the Control of Protein Expression in Space and Time 140 5.1 Introduction 141 5.2 The C. elegans System as a Tool for Investigating Spatiotemporal Control of Translation 142 5.3 C. elegans Germline RNP Granules 144 5.4 Translational Activation of mRNAs During the Oocyte-to-Embryo Transition 145 5.5 Cytoplasmic Polyadenylation Is Key to Activation of Silent mRNA 146 5.6 Scaling 3′-UTR Regulatory Capacity with Complexity 149 5.7 Future Directions for Dissection of the Information Content of 3′-UTR 151 References 152 Chapter 6: Communication Is Key: 5′-3′ Interactions that Regulate mRNA Translation and Turnover 156 6.1 The Genesis of the Closed-Loop Model 156 6.2 5′ Cap- and 3′ Poly(A) Tail-Dependent Translation 157 6.3 Poly(A) Tail-Independent mRNA Translation 159 6.4 Long-Distance RNA-RNA Interactions that Support Cap- and Poly(A) Tail-Independent Translation 160 6.5 5′-3′ Interactions that Repress mRNA Translation 161 6.6 Conclusions and Future Perspectives 166 References 167 Chapter 7: Bioinformatics Approaches to Gain Insights into cis-Regulatory Motifs Involved in mRNA Localization 172 7.1 General Introduction 173 7.2 Fundamental Aspects of RNA Localization 174 7.2.1 cis-Regulatory Motifs Implicated in RNA Localization 175 7.3 Representation and Information Content of Sequence Motifs 180 7.4 Algorithms and Tools for Finding Motifs 183 7.4.1 Fundamentals of Major Motif Discovery Algorithms 183 7.4.2 Overview of Existing Computational Tools to Search for CRMs 186 7.5 Examples of Motif Discovery Applications 189 7.6 Conclusion 192 References 192 Chapter 8: RNA Granules and Their Role in Neurodegenerative Diseases 202 8.1 Introduction 202 8.1.1 RNA-Binding Proteins 203 8.1.2 RBP Aggregation 204 8.2 Stress Granules 205 8.3 Processing Bodies 209 8.4 Transport Granules 212 8.5 Neurodegenerative Disease 214 8.5.1 Stress Granules and ALS 224 8.5.2 Stress Granules and Alzheimer ́s Disease and Tauopathies 229 8.5.3 Processing Bodies and ALS 231 8.5.4 Processing Bodies and Alzheimer ́s Disease and Tauopathies 232 8.5.5 Transport RNA Granules in ALS 234 8.5.6 Transport Granules and Alzheimer ́s Disease 235 8.6 Concluding Remarks 236 References 236 Chapter 9: Lessons from (pre-)mRNA Imaging 253 9.1 Tools for RNA Visualization at Different Scales 254 9.1.1 RNA Detection in Fixed Cells and Tissues 254 9.1.2 RNA Detection in Living Cells 258 9.2 Visualizing Nuclear (pre-)mRNPs 260 9.2.1 RNA Imaging to Study Transcription Initiation and Elongation 262 9.2.2 Pre-mRNA Maturation 264 9.2.3 Organization and Movement of mRNPs Within the Nucleoplasm 266 9.2.4 mRNP Export Through the Nuclear Pore Complex 268 9.3 Visualizing Cytoplasmic mRNPs 269 9.3.1 Discovery of mRNA Localization and Local mRNA Translation 269 9.3.2 Dynamics of Translation Initiation and Elongation 272 9.3.3 Spatial Organization of Translating mRNAs 275 9.3.4 Spatial Organization of Translationally Inhibited RNAs 276 9.3.5 Towards Death of an mRNA 276 9.4 Outlook 279 References 281 Chapter 10: Diverging RNPs: Toward Understanding lncRNA-Protein Interactions and Functions 291 10.1 Introduction 292 10.2 Nuclear Functions of lncRNAs 295 10.2.1 Transcriptional Regulation 295 10.2.1.1 Regulating Transcription in cis 295 10.2.1.2 Transcription Regulation in trans 298 10.2.2 Chromatin Architecture and Nuclear Organization 299 10.2.3 Post-transcriptional Regulation: Splicing and RNA Editing 300 10.3 Cytoplasmic Functions of lncRNAs 301 10.3.1 Protein Localization 302 10.3.2 Translation Regulation 302 10.3.3 Regulating RNA Stability 303 10.3.4 Protein Signaling and Activation 304 10.4 Characterizing lncRNA-Protein Interactions 304 10.4.1 Protein-Centric Approaches 305 10.4.1.1 RNA Immunoprecipitation (RIP) 305 10.4.1.2 Cross-Linking Immunoprecipitation (CLIP) 307 10.4.2 RNA-Centric Approaches 308 10.4.2.1 RNA Pulldown 308 10.4.2.2 Biotinylated Oligo Approaches (ChIRP-MS, CHART-MS, RAP-MAS) 308 10.4.2.3 Aptamer-Based Approaches 309 10.5 Concluding Remarks 310 References 311 Front Matter ....Pages i-viii Mechanism and Regulation of Co-transcriptional mRNP Assembly and Nuclear mRNA Export (Wolfgang Wende, Peter Friedhoff, Katja Sträßer)....Pages 1-31 It’s Not the Destination, It’s the Journey: Heterogeneity in mRNA Export Mechanisms (Daniel D. Scott, L. Carolina Aguilar, Mathew Kramar, Marlene Oeffinger)....Pages 33-81 View from an mRNP: The Roles of SR Proteins in Assembly, Maturation and Turnover (Marius Wegener, Michaela Müller-McNicoll)....Pages 83-112 The Nuclear RNA Exosome and Its Cofactors (Manfred Schmid, Torben Heick Jensen)....Pages 113-132 3′-UTRs and the Control of Protein Expression in Space and Time (Traude H. Beilharz, Michael M. See, Peter R. Boag)....Pages 133-148 Communication Is Key: 5′–3′ Interactions that Regulate mRNA Translation and Turnover (Hana Fakim, Marc R. Fabian)....Pages 149-164 Bioinformatics Approaches to Gain Insights into cis-Regulatory Motifs Involved in mRNA Localization (Louis Philip Benoit Bouvrette, Mathieu Blanchette, Eric Lécuyer)....Pages 165-194 RNA Granules and Their Role in Neurodegenerative Diseases (Hadjara Sidibé, Christine Vande Velde)....Pages 195-245 Lessons from (pre-)mRNA Imaging (Srivathsan Adivarahan, Daniel Zenklusen)....Pages 247-284 Diverging RNPs: Toward Understanding lncRNA-Protein Interactions and Functions (Martin Sauvageau)....Pages 285-312