RNA and DNA Editing: Molecular Mechanisms and Their Integration into Biological Systems / Edition 1

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RNA and DNA Editing assembles a team of leading experts who present the latest discoveries in the field alongside the latest models and methodology. In addition, the authors set forth the many open questions and suggest routes for further investigation. Overall, the book serves as a practical guide for professionals in the field who need to understand the interrelationship of RNA and DNA editing with other chemical and biological processes.

This book not only discusses the current states of research in depth, it also gives new contributors an opportunity to express their vision. The perspectives voiced by these authors are provocative and intended to motivate discussion and inspire new experiments. Finally, this book will promote new hypotheses and models that can serve as springboards for the next generation of discoveries in the field.

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Editorial Reviews

From the Publisher
"This volume is a very good compilation of the state of the art in RNA and DNA editing, and will be useful and fascinating reading for both researchers in the field and anyone with an interest in joining it." (The Quarterly Review of Biology, June 2009)
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Product Details

  • ISBN-13: 9780470109915
  • Publisher: Wiley, John & Sons, Incorporated
  • Publication date: 2/15/2008
  • Edition number: 1
  • Pages: 438
  • Product dimensions: 6.44 (w) x 9.43 (h) x 1.14 (d)

Meet the Author

Harold C. Smith, PhD, is Professor in the Department of Biochemistry and Biophysics at the University of Rochester and the founder and Chief Scientific Officerof OyaGen, a biotech company that develops drugs that target editing enzymes. Dr. Smith organized the first Gordon Research Conference on RNA Editing in 1997 and holds four patents.

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Table of Contents

Preface     xv
Acknowledgments     xix
Contributors     xxi
Diversification of the Proteome Through RNA and DNA Editing
Diversifying Exon Code Through A-to-I RNA Editing     3
Introduction and Background     3
Initial Discovery and Context of A-to-I RNA Editing and ADARs     4
Important Cases of Recoding by A-to-I Modification in Pre-mRNA     5
Cis-Acting Features for A-to-I Editing     14
Properties of the A-to-I Editing Machinery     15
Main Questions in the Field and Approaches     17
Biochemical Versus Computational Approaches     17
Editing of miRNA Sequences     21
Future Directions: Evolution of Editing Sites and Machinery     23
References     24
Antibody Gene Diversification by Aid-Catalyzed DNA Editing     31
Introduction     31
Before AID     32
Without DNA (Darkness) and with DNA (Light)     32
Prominent Early Models for Antibody Diversification     32
How Protein Sequencing Technology Enabled an Understanding of Antibody Diversity     34
Somatic DNA Rearrangements Underpin V(D)J Joining and Create the Primary Antibody Repertoire     37
Additional Antibody Diversity by Somatic Hypermutation (and GeneConversion in Some Animals)     40
Altering Antibody Function by Class Switch Recombination (Isotype Switching)     40
After AID     41
A Novel Deaminase Is Required for CSR, SHM, and IGC     41
AID Is a DNA Cytosine Deaminase that Directly Triggers Antibody Diversification     43
The Importance of Uracil Bases in DNA In Vivo     45
Processing of AID-induced Lesions: The Molecular Mechanism of Somatic-Hypermutation     48
Processing of AID-induced Lesions: The Molecular Mechanism of Immunoglobulin Gene Conversion     49
Processing of AID-induced Lesions: The Molecular Mechanism of Class Switch Recombination     50
Hot Areas and Speculations     53
Immunodeficiency Syndromes Caused by Defects in AID-Mediated Ig Gene Diversification     53
Regulating the DNA Mutator Activity of AID     54
Misregulation of AID and Cancer     57
AID Is But One Member of a Much Larger Family of Polynucleotide Deaminases     58
Conclusions     60
Acknowledgments     60
References     61
Protein-Protein and RNA-Protein Interactions in U-Insertion/Deletion RNA Editing Complexes     71
A Bizarre Phenomenon and its Raison D'etre     71
The Catalytic Mechanism and Machinery      73
Extent of U-Insertion/Deletion RNA Editing in Trypanosoma and Leishmania Species     75
Functional Studies of Editing Complex Subunits     76
REN1, REN2, and MP67. Endonuclease Homologs     80
REX1 and REX2. Exonuclease Homologs     83
RET2. TUTase     85
REL1 and REL2. Ligase Homologs     85
MP81, MP63, MP42, MP46, MP44, MP24, MP18. Structural Components     87
RNA-Protein Interactions: Isolated Subunits and Assembled Editing Complexes     92
MP42     92
MP24     93
RNA-Protein Interactions in Assembled Editing Complexes     93
Concluding Remarks     96
Acknowledgments     96
References     96
Machinery of RNA Editing in Plant Organelles     99
Introduction     99
Mechanism of Target Recognition     100
PPR Protein is a Trans-Factor in Plastids     101
How Can the Model Be Generalized to Plant RNA Editing?     104
Can Closely Located Editing Sites Share a Trans-Factor?     105
Is a Trans-Factor Specific to a Single Cis-Element?     106
Mechanism Determining the Efficiency of RNA Editing     107
Co-Evolution of Trans-Factors and Editing Sites     109
What is an Editing Enzyme?     110
A Model of Editing Machinery in Plastids     112
Future Directions     114
Acknowledgments     114
References     114
Functional Coordination of RNA Editing with Other Cellular Mechanisms
Transfer RNA Editing Enzymes: at the Crossroads of Affinity and Specificity     123
Introduction: Structural Versus Functional tRNA Editing     123
Transfer RNA Editing for Structure     124
C-to-U Editing of the tRNA Backbone     124
A-to-I Editing and Modification at Position 37 and 57 of tRNAs     126
Transfer RNA Editing for Function     127
The Lysidine Story     127
Nucleotide Additions at the Ends of tRNAs     130
C-to-U Editing in Marsupials and Trypanosomatids     133
A-to-I Editing of tRNAs in Yeast and Bacteria     137
Double Editing in Trypanosomatids     139
The Transfer RNA Editing Enzymes of Trypanosomatids: A Special Case of Catalytic Flexibility     140
Complex Formation by Transfer RNA Editing Enzymes: A Model for the Regulation of Editing Activity     141
Concluding Remarks: Evolution of Transfer RNA Editing Deaminases: Affinity Versus Specificity     142
References     143
A-to-I Editing as a Co-Transcriptional RNA Processing Event     146
Introduction     146
Overview of Co-transcriptional Pre-mRNA Processing     147
Localization of the ADAR Proteins     148
A-to-I Editing as a Pre-mRNA Processing Event     149
Main Questions in the Field and Approaches     149
Why Are Edited Sites Often Situated Close to Exon/Intron Border?     149
The Potential of A-to-I Editing in Changing the Transcriptome     151
RNA Editing, the Influence on Pre-mRNA Splicing and Vice Versa     152
Can Editing Influence the Fate of a Messenger RNA in Other Ways?     156
Editing and Its Potential Effect on RNA Export     156
Editing as a Modulator of RNA Stability     156
Editing and Its Influence on Polyadenylation     157
Prospectives for Future Research     158
References     159
Studying and Working with Ribonucleoproteins that Catalyze H/ACA Guided RNA Modification     162
Introduction     162
Discovery of Complex (RNA-guided) Pseudouridine Synthases     164
Approaches and Challenges     164
RNP Reconstitution     166
Lessons from Archaeal H/ACA RNPs     167
Biogenesis of Eukaryotic H/ACA RNPs     168
Debate on Dyskeratosis Congenita     168
Importance and Future of H/ACA RNPs     169
Acknowledgments     170
References     171
Functional Roles of Spliceosomal snRNA Modifications in Pre-mRNA Splicing     175
Introduction     175
Modified Nucleotides in Spliceosomal snRNAs     176
Functional Analysis of Spliceosomal snRNA Modifications     179
Modified Nucleotides of U2 snRNA are Important for Pre-mRNA Splicing     180
U2 Modifications Contribute to snRNP Biogenesis and Spliceosome Assembly     182
Genetic Analysis of U2 Modification in Yeast     183
Cytotoxicity Associated with 5FU Treatment is a Result of Inhibition on Pseudouridylation and Splicing     184
Biophysical Analysis of U2 snRNA Modification     185
Concluding Remarks     186
References     186
A Role for A-to-I Editing in Gene Silencing     190
Expression of Double-Stranded RNA in Cells     190
The Activity of ADAR in the Nucleus     191
Alternative Fates of Edited RNAs in the Nucleus     192
A Possible Connection Between RNA Editing and Gene Silencing     193
Heterochromatin     193
RNAi-Directed Heterochromatin Formation     194
Connections Between RNAi and dsRNA Editing     196
Vigilin     196
Recognition of RNA by Vigilins     197
The Vigilin Complex     198
A Model for the Nuclear Function of Vigilin     199
References     200
Biological Implications and Broader-Range Functions for Apobec-1 and Apobec-1 Complementation Factor (ACF)     203
Overview     203
Background to Our Current Understanding of C-to-U Editing of ApoB mRNA: Canonical Functions for Apobec-1 and ACF     204
Role of Cis-Acting Elements     204
Identification and Characterization of Trans-Acting Factors     206
Current Understanding of Apobec-1 and ACF: Structure-Function and Genetic Regulation     209
Apobec-1: Structure-Function Relationships     209
Functions of Apobec-1 Beyond apoB mRNA Editing     210
Apobec-1: Genetic Regulation and Gain- and Loss-of-Function     212
ACF: Structure-Function Relationships     214
Intersections of Apobec-1 and ACF Regulation in the Modulation of C-to-U RNA Editing     216
Implications and Broad-Range Function for Apobec-1 and ACF: Future Directions and Overarching Questions     218
Apobec-1     218
ACF     220
Conclusions     224
Acknowledgments      224
References     224
Antiviral Function of Apobec3 Cytidine Deaminases     231
Explanation of Vif Phenotype Uncovers a Unique Innate Resistance to HIV-1 Infection     231
Antiviral Functionality of the APOBEC3 Family of Proteins     232
Mechanism of Action     232
APOBEC3 Proteins and the Prevention of Zoonosis     235
In Vivo Correlations Between APOBEC3 Expression and Disease Course     236
The Battle for Control: Viral Suppression of the APOBEC3 Proteins     237
The Hijacking of the Proteasomal Degradation Pathways     237
Virion Exclusion of the APOBECs via a Viral-Dependent Mechanism     238
Cellular Function and Regulation of the APOBEC3 Family     238
Guardians of the Genome: APOBEC3-Mediated Suppression of Cellular Retroelements     238
Subcellular Localization (Sequestration)     239
Control of the Expression of the APOBEC3 Family is Exerted Transcriptionally     240
Research Questions and the Hope of Therapeutic Manipulation of the APOBEC3 Family     243
The "Alternative Function"     244
Protein Partitioning/Subcellular Localization     245
Protein Cofactors and Posttranslational Modifications     245
Therapeutic Potential      246
References     247
Predictive Structures
A-to-I Editing of Alu Repeats     257
Background     257
Indirect Evidence for Abundant A-to-I Editing     257
Early Screens for A-to-I Editing Targets     258
The Alu Repeats     259
Computational Detection of A-to-I Editing     260
Sifting through db EST     260
Clusters of Mismatches in RNAs     262
Numbers of Editing Sites Detected     265
Characterization of the Edited Transcripts     265
Looking for Conserved Polymorphism Sites     267
Additional Potential Targets for Abundant A-to-I Editing     267
Editing in Other Organisms     268
Uniqueness of the Alu Repeat     269
Predicting Editing Sites from Genomic Data     270
Biological Role of Alu Editing     272
Possible Regulatory Roles     272
Alu Editing and miRNA     272
Alternative Splicing and Alu Editing     273
Concluding Remarks     275
References     276
RNA Editing in Dinoflagellates and Its Implications for the Evolutionary History of the Editing Machinery     280
Introduction     280
Inferred RNA Editing in Dinoflagellates     283
cob and cox1 mRNA     283
Chloroplast Transcripts     288
Biochemical Characteristics of Editing     289
Unusually Diverse Types of Editing     289
Varying Editing Density and Discrete Distribution of Editing Events in Coding Sequences     293
Markedly Nonrandom Distribution in the Type of Codon Edited and in the Position of the Editing Site Within Codons     294
Consequences of Editing     297
Phylogenetic Trend     301
Implications for the Origin and Evolution of the RNA Editing Machinery     304
Acknowledgment     306
References     306
Structural Approaches
The Box C/D RNPs: Evolutionarily Ancient Nucleotide Modification Complexes     313
Introduction     313
Diversity of Box C/D RNA Populations     314
Box C/D RNA Nomenclature     314
Box C/D RNA Structure     315
Diversity of Box C/D RNA Populations     316
Box C/D RNA Identification     316
Box C/D RNA Functions and Target RNAs     319
Folding and Cleavage of Pre-rRNA     319
2'-O-Methylation of Diverse RNA Targets     319
Additional Roles and Targets for Box C/D RNAs     320
Box C/D RNP Structure and Nucleotide Methylation Function     321
Eukaryotic Box C/D Core Proteins and snoRNP Structure     321
Archaeal Box C/D Core Proteins and In Vitro sRNP Assembly     322
Emerging Core Protein and RNP Crystal Structures     322
Investigating Methylation Function Using In Vitro Assembled Archael Box C/D sRNP     323
Box C/D RNP Biogenesis     323
Genomic Organization of Eukaryotic Box C/D snoRNA Genes     323
Independently Transcribed and Intronic Eukaryotic Box C/D snoRNA Genes     324
Archaeal Box C/D sRNA Genes     324
Transcription and Processing of Independently Transcribed Box C/D snoRNAs     325
Transcription and Processing of Intronic Box C/D snoRNAs     326
Box C/D snoRNP Transport     327
Future Directions and Experimental Challenges     327
Box C/D RNA Diversity, Targets, and Functions     327
Box C/D RNP Structure and Methylation Function     328
Box C/D RNP Biogenesis     330
Acknowledgments     331
References     331
Structural Features of the Adar Family of Enzymes and Their Substrates     340
ADAR Enzymes     340
Overview and Functions of ADARs     341
Double-Stranded RNA Binding Domains (dsRBDs)     344
Xenopus laevis XIrbpa     345
ADAR2 dsRBD1 and dsRBD2     346
Deaminase Domain     346
Z[alpha] and Z[beta] Domains     347
Z[alpha] Structure     349
Z[beta] Structure     351
Structural Comparison of Z[alpha] and Z[beta]     354
Conclusions     354
Substrates     355
Overview and General Features     355
Double-Stranded RNA Targets and Structural Features     355
Site-Selective A-to-I Editing     355
Structural Features of Site-Selective A-to-I Editing     358
Promiscuous Editing     359
Single-stranded RNA Targets     361
Z-DNA and Z-RNA Targets     361
Future Directions     362
References     362
Chemistry, Phylogeny, and Three-Dimensional Structure of the Apobec Protein Family     369
Introduction to Nucleic Acid Deamination with Implications for Biological Activity     369
The Chemistry of the Zinc-Dependent Deaminase Amino Acid Signature Motif     370
The ZDD Signature Motif Implies a Specific Three-Dimensional Arrangement of Amino Acids     371
Rationale for a Combined Structural and Phylogenetic Approach to Understand APOBEC Evolution      373
The Starting Point for Structural and Phylogenetic Analyses of APOBEC Family Members     375
The CDA Superfamily: Overview of Conserved Fold Topology in the Core and Common Variations     379
Comparison of the Common CDA Superfamily Core Reveals Broad Peripheral Diversification     381
Modes of Oligomerization     382
Free Nucleotide Cytidine Deaminases (CDA): Strand [beta]5 Antiparallel to Strand [beta]4     382
Cytosine Deaminase, Guanine Deaminase, and TadA: Strand [beta]5 Parallel to [beta]4     382
Deoxcytidylate Deaminases (T4, N. e) and APOBEC2: Strand [beta]5 Parallel to [beta]4     383
Multidomain Enzymes RibG and ADAR2 of the CDA Superfamily: Strand [beta]5 Parallel to [beta]4     387
Modes of Substrate Interaction     388
Tetrameric fnCDAs Favor Flexible Flaps: RNA Editing and the Case of Cdd1 from Yeast     390
A Topological Transformation Obstructs Active Site Accessibility in Dimeric Deaminases that Bind Bases     391
Substrate Selection by Polynucleotide Editing Enzymes Remains Elusive     391
The APOBEC Family: Insights into a Structurally Underrepresented Family     392
Activation-Induced Deaminase (AID)-an Ancient Enzyme with Essential Roles in Adaptive Immunity     395
APOBEC2-A Divergent Ancestral Protein of Unknown Function      396
APOBEC1-The Historical Archetype of C-to-U Editing Enzymes     397
APOBEC4-Pushing the Envelope of APOBEC Boundaries     399
APOBEC3-Radiative Expansion of Proteins Involved in Viral Defense     400
Mechanisms of Primate-Specific Expansion of the APOBEC3 Proteins     402
Alternative Methods to Obtain Structure: The Molecular Envelope of APOBEC3G by Small-Angle X-Ray Scattering     405
Characterization of Structural Changes in APOBEC3G Morphology in the Presence of RNA     406
Positive Selection Exerted on the APOBEC3 Family     408
Conclusions and Future Prospects     410
References     411
Index     421
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