Reflecting the rapid progress in the field, the book presents the current understanding of molecular mechanisms of post-transcriptional gene regulation thereby focusing on RNA processing mechanisms in eucaryotic cells. With chapters on mechanisms as RNA splicing, RNA interference, MicroRNAs, RNA editing and others, the book also discusses the critical role of RNA processing for the pathogenesis of a wide range of human diseases. The interdisciplinary importance of the topic makes the title a useful resource for a wide reader group in science, clinics as well as pharmaceutical industry.

Jane Y. Wu is the Charles Louis Mix Professor in the Department of Neurology, the Lurie Cancer Center and the Center for Genetic Medicine at Northwestern University in Chicago, USA as well as a senior consulting investigator at the Chinese Academy of Science, Beijing, China. After obtaining her doctorate from Stanford University and her postdoctoral training at Harvard University, Dr. Wu has been focusing on studying molecular mechanisms controlling gene regulation, in particular, those critical for neural development and neurodegeneration. Her research has significantly advanced our understanding of the fundamental role of RNA processing in biology and in human pathogenesis.

ForewordXI

List of ContributorsXIII

1 The Role of Cotranscriptional Recruitment of RNA-Binding Proteins in the Maintenance of Genomic Stability1Jennifer A. Aoki and James L. Manley

1.1 Introduction1

1.2 THO/TREX2

1.3 Linking Transcription to Export of mRNP4

1.4 Cotranscriptional R-loop Formation7

1.5 R-loop-induced Double-Stranded (ds) DNA Breaks10

1.6 Concluding Remarks12

References12

2 Transcription Termination by RNA Polymerase II19Minkyu Kim and Stephen Buratowski

2.1 Messenger RNA Gene Termination19

2.2 Small Nucleolar RNA Gene Termination Pathway23

2.3 Choice between the Two Termination Pathways25

2.4 Regulation of Transcription by Termination27

2.5 Mechanisms of Termination by Other RNA Polymerases30

2.6 Future Perspectives31

Acknowledgments32

References32

3 Posttranscriptional Gene Regulation by an Editor: ADAR and its Role in RNA Editing41Louis Valente, Yukio Kawahara, Boris Zinshteyn, Hisashi Iizasa, and Kazuko Nishikura

3.1 Introduction41

3.2 The RNA Editing Kinship44

3.3 The ADAR Gene Family45

3.4 The Role of RNA in the A-to-I Editing Mechanism51

3.5 Splice Site Alterations52

3.6 A-to-I RNA Recoding Modifies Proteins Such As Neurotransmitters55

3.7 Cellular Effects andin VivoPhenotypes of ADAR Gene Inactivation59

3.8 Noncoding RNA and Repetitive Sequences61

3.9 Effects on the RNA Interference Silencing Pathway64

3.10 Effects on MicroRNA Processing and Target Selection66

3.11 RNA Editing Role as an Antiviral Mechanism67

3.12 Conclusions68

Acknowledgments69

References69

4 Posttranslational Modification of Sm Proteins: Diverse Roles in snRNP Assembly and Germ Line Specification83Graydon B. Gonsalvez and A. Gregory Matera

4.1 Introduction83

4.2 Protein Methylation Flavors and Functions84

4.3 Sm Proteins Contain sDMA- and aDMA-Modifi ed Arginines86

4.4 SnRNP Assembly, the Survival Motor Neuron (SMN) Complex, and Spinal Muscular Atrophy (SMA)87

4.5 PRMT5 and PRMT7 The Sm Protein Methyltransferases89

4.6 Sm Protein Methylation is Required for sn/RNP Assembly in Mammals92

4.7 Sm Protein Methylation inDrosophila 94

4.8 Unresolved Questions: Sm Protein Methylation and snRNP Assembly95

4.9 Conclusion The Evolution of snRNP Assembly96

4.10 Sm Proteins Are Required for Germ Cell Specification97

4.11 Dart5, Valois, Sm Proteins, and Tudor Anchoring100

4.12 Unresolved Questions: Sm Proteins and Germ Cell Specification101

4.13 The Transcriptional Functions of PRMT5102

4.14 Arginine Methylation No Longer in the Shadow of Phosphorylation103

4.15 Sm Proteins Doughnut-Shaped Relics of Our RNA Past104

References106

5 Structure, Function, and Biogenesis of Small Nucleolar Ribonucleoprotein Particles117Katherine S. Godin and Gabriele Varani

5.1 Introduction117

5.2 The Guide RNA119

5.3 The Core sno/sRNP Proteins120

5.4 Assembly and Structural Organization of sno/sRNPs122

5.5 Asymmetric Assembly, Structure, and Activity of the Box C/D122

5.6 The Box H/ACA RNP Structure and Assembly of the Eukaryotic RNP125

5.7 Summary128

References128

6 Mechanistic Insights into Mammalian Pre-mRNA Splicing133Sebastian M. Fica, Eliza C. Small, Melissa Mefford, and Jonathan P. Staley

6.1 Introduction133

6.2 Chemistry of Splicing133

6.3 Composition and Assembly of the Spliceosome135

6.4 Control of Spliceosome Assembly and Activation139

6.5 Spliceosome Structure and Dynamics141

6.6 The Structure of the Spliceosomal Active Site and the Mechanism of Catalysis145

6.7 Fidelity in Splicing149

6.8 Concluding Remarks151

Acknowledgments152

References152

7 Splicing Decisions Shape Neuronal Protein Function across the Transcriptome163Jill A. Dembowski and Paula J. Grabowski

7.1 Introduction163

7.2 A Diversity of RNA-Binding Protein Regulators165

7.3 Gene-Specific and Global Experimental Approaches to Splicing Mechanisms167

7.4 Alternative Splicing ofDscamPre-mRNA: Mechanism and Significance for the Development of Neuronal Circuits169

7.5 The NMDA R1 Receptor: Brain-Region-Specific and Activity-Dependent Splicing171

7.6 Alternative Splicing Response to Neuronal Excitation172

7.7 Splicing Silencing by PTB: Versatility of Mechanism and Cross-Regulation of nPTB173

7.8 Upstream Regulation of Splicing Factors by MicroRNAs175

7.9 Conclusions and Prospects176

Acknowledgments177

References177

8 Noncoding RNA: The Major Output of Gene Expression181Matthias Harbers and Piero Carninci

8.1 Introduction181

8.2 What is ncRNA?182

8.3 Discovery of ncRNAs182

8.4 ncRNA Families190

8.5 Examples for ncRNA Functions196

8.6 Perspectives200

8.7 Note Added in Proof202

Acknowledgments202

References203

9 Noncoding RNAs, Neurodevelopment, and Neurodegeneration215Mengmeng Chen, Jianwen Deng, Mengxue Yang, Kun Zhu, Jianghong Liu, Li Zhu, and Jane Y. Wu

9.1 Introduction215

9.2 Expression of ncRNAs in the Nervous System215

9.3 ncRNAs in Neurodevelopment218

9.4 ncRNAs in Neurodevelopmental and Neuropsychiatric Diseases219

9.4.1 MicroRNAs and Neurodevelopmental Disorders220

9.5 ncRNAs in Neurodegeneration224

9.6 Concluding Remarks and Perspectives227

Acknowledgments228

References228

Further Reading236

10 The Evolution of the Modern RNA World239Ying Chen, Hongzheng Dai, and Manyuan Long

10.1 Evolution of Noncoding RNA Gene239

10.2 Evolution of Transcriptional Regulation242

10.3 Evolution of Posttranscriptional Gene Regulation243

10.4 Phenotypic Evolution by the Origination of New ncRNA Genes and Perspectives between Protein-Coding and ncRNA Genes247

References249

Index253