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Contents

Some Articles Planned for Future Volumes ix

Molecular Regulation, Evolutionary, and Functional Adaptations Associated with C to U Editing of Mammalian ApolipoproteinB mRNA 1

Shrikant Anant, Valerie Blanc, and Nicholas O. Davidson I. RNA Editing: General Overview of Underlying Biochemical

Mechanisms and Evolutionary Development 2

II. C to U RNA Editing 5

III. C to U ApoB RNA Editing: cis-Acting Elements 14

IV. C to U ApoB RNA Editing: trans-Acting Factors 17

Acknowledgments 33

References 33

Polymorphisms in the Genes Encoding Members of the Tristetraprolin Family of Human Tandem CCCH Zinc Finger Proteins 43

Perry J. Blackshear, Ruth S. Phillips, Johana Vazquez-Matias, and Harvey Mohrenweiser

I. Introduction 44

II. Materials and Methods 45

III. Results 52

IV. Discussion 63

Acknowledgments 66

References 66

Molecular and Cell Biology of Phosphatidylserine and Phosphatidylethanolamine Metabolism 69

Jean E. Vance

I. Membrane Phospholipids 70

II. Pathways for Biosynthesis of Phosphatidylserine and

Phosphatidylethanolamine 71

III. Enzymes of Phosphatidylserine Biosynthesis 74

IV. Enzymes of Phosphatidylethanolamine Biosynthesis 82

V. Regulation of PS and PE Biosynthesis 85

VI. Interorganelle Transport of PS and PE 87

VII. Intramembrane Transport of PS and PE 92

VIII. Biological Functions of PS and PE 95

IX. Future Directions 97

References 98

DNA-Protein Interactions during the Initiation and Termination of Plasmid pT181 Rolling-Circle

Replication 113

Saleem A. Khan

I. Introduction 114

II. Origins of Replication of the Plasmids of the pT181 Family 116

III. Initiator Proteins of the Plasmid pT181 Family 122

IV. Mechanism of Inactivation of the Plasmid pT181 Family Rep Proteins . 126 V. Role of Host Proteins in pT181 RC Replication 129

VI. Replication of the Lagging Strand of Plasmid pT181 132

VII. Conclusions and Future Directions 133

Acknowledgments 133

References 133

Herpes Simplex Virus Type-1: A Model for Genome

Transactions 139

Paul E. Boehmer and Giuseppe Villani

I. Introduction to Herpesviridae 140

II. HSV-1 Life Cycle, Genome Structure, and Replication Genes 140

III. Initiation of Replication 144

IV. Elongation 151

V. Interaction of the HSV-1 DNA Replication Machinery with

DNA Damage 155

VI. Homologous Recombination 159

VII. Concluding Remarks 163

Acknowledgments 165

References 165

Enzymology and Molecular Biology of Glucocorticoid

Metabolism in Humans 173

Andreas Blum and Edmund Maser

I. Introduction 174

II. Glucocorticoid Action 175

III. The Free Hormone Hypothesis 177

IV. Glucocorticoid Receptors 178

V. Nongenomic Action of Glucocorticoids 179

VI. Glucocorticoid Resistance 180

VII. 11^-Hydroxysteroid Dehydrogenase (11^-HSD) as

Prereceptor Control 181

VIII. Hydroxysteroid Dehydrogenases: Physiological Role 182

IX. The History of Two Isoforms: 11^-HSD Type 1 and

11^-HSD Type 2 182

X. A (Patho)physiological Role for 11^-HSD 1 and 11^-HSD 2 183

XI. 11^-HSD 2 and the Syndrome of "Apparent Mineralocorticoid

XII. 11 ^-Hydroxysteroid Dehydrogenase Type 1 (11^-HSD 1) 187

XIII. Conclusions 203

References 203

Dancing with Complement C4 and the RP-C4-CYP21 -TNX

(RCCX) Modules of the Major Histocompatibility

Complex 217

C. Yung Yu, Erwin K. Chung, Yan Yang, Carol A. Blanchong, Natalie Jacobsen, Kapil Saxena, Zhenyu Yang, Webb Miller, Lilian Varga, and George Fust

I. Introduction 219

II. The Sophisticated Genetic Diversities of Human C4

and RCCX Modules 221

III. Structural Diversities of the Human and Mouse C4 Proteins 232

IV. Nucleotide Polymorphisms in Human C4A and C4B Genes 245

V. Expression of C4A and C4B Transcripts and Proteins 255

VI. The Endogenous Retrovirus that Mediates the Dichotomous Size

Variation of C4 Genes 260

VII. Evolution of Complement C3/C4/C5 and the RCCX Modules in the MHC 267

VIII. Afterthoughts: Eleven Outstanding Issues to be Addressed 274

Acknowledgments 276

References 276

The Roles and Regulation of Potassium in Bacteria . . . 293

Wolfgang Epstein

I. Paths of K+ Movement 296

II. Regulation of K + Transport Systems 305

III. K As An Intracellular Activator 309

IV. Regulation of Internal pH by K+ 311

V. Future Directions 312

References 313

Conformational Polymorphism of d(A-G)n and Related

Oligonucleotide Sequences 321

Nina G. Dolinnaya and Jacques R. Fresco

I. Introduction 321

II. a-DNA HelixQAcid-Dependent Duplex Equilibrium 323

III. Acid-Dependent Parallel DuplexQpH-Independent Parallel

Duplex Equilibrium 332

IV. pH-Independent Parallel DuplexQSingle-Hairpin DuplexQTwo-Hairpin Tetraplex Equilibria 334

V. Concluding Remarks 342

Acknowledgments 344

References 344

Index 349

Some Articles Planned for Future Volumes

Clamp and Clamp Loaders in Eukaryotic DNA Metabolism

Peter M. J. Burgers

Ccr4-Not Complex: A Regulatory Platform for Several Cellular Machineries

Martine A. Collart and Marc Timmers

DNA Methylation and the Regulation of Vertebrate Gene Expression

Gordon D. Ginder

The Yeast 2 Micron Plasmid: A Model for Opitimized Molecular Selfishness

Makkuni Jayaram, Yuri Vaziyanov and Soundarapandian Velmurugan

Translational Control of Gene Expression by Hormones and Nutrients

Leonard S. Jefferson and Scot R. Kimball

The Possible Origin of Features that Set Apart the Eukaryal and Prokaryal Replication Forks

Gabriel Kaufmann and Tamar Nethanel

FGF3: a Gene with a Finely Tuned Spatiotemporal Pattern of Expression During Development

Christian Lavialle

Specificity and Diversity in DNA Recognition by E. coli Cyclic AMP Receptor Protein

James C. Lee

Oxygen Sensing and Oxygen-Regulated Gene Expression in Yeast

Robert O. Poyton

Ribonucleases in Cancer Chemotherapy

Robert T. Raines, P. A. Leland, M. C. Herbert and K. E. Staniszewski

Broad Specificity of Serine/Arginine (SR)-Rich Proteins Involved in the Regulation of Alternative Splicing of Premessenger RNA

James Stevenin, Cyril Bourgeois and Fabrice Lejune

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Molecular Regulation, Evolutionary, and Functional Adaptations Associated with C to U Editing of Mammalian ApolipoproteinB mRNA

Shrikant Anant,*

Valerie Blanc,* and Nicholas

O. Davidson*

*Department of Internal Medicine; and y Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA

I. RNA Editing: General Overview of Underlying Biochemical

Mechanisms and Evolutionary Development 2

III. C to U ApoB RNA Editing: cis-Acting Elements 14

IV. C to U ApoB RNA Editing: trans-Acting Factors 17

V. Summary 33

Acknowledgments 33

References 33

RNA editing encompasses an important class of co- or posttranscriptional nucleic acid modification that has expanded our understanding of the range of mechanisms that facilitate genetic plasticity. Since the initial description of RNA editing in trypanosome mitochondria, a model of gene regulation has emerged that now encompasses a diverse range of biochemical and genetic mechanisms by which nuclear, mitochondrial, and t-RNA sequences are modified from templated versions encoded in the genome. RNA editing is genetically and biochemically distinct from other RNA modifications such as splicing, capping, and polyadenylation although, as discussed in Section I, these modifications may have relevance to the regulation of certain types of mammalian RNA editing. This review will focus on C to U RNA editing, in particular, the biochemical and genetic mechanisms that regulate this process in mammals. These mechanisms will be examined in the context of the prototype model of C to U RNA editing, namely the posttranscriptional cytidine deamination targeting a single nucleotide in mammalian apolipoproteinB (apoB). Other examples of C to U RNA editing will be discussed and the molecular mechanisms—where known— contrasted with those regulating apoB RNA editing. © 2003 Elsevier Science

Progress in Nucleic Acid Research and Molecular Biology, Vol. 75

Copyright O 2003 Elsevier, Inc. All rights of reproduction in any form reserved.

ISSN: 0079-6603/2003 $35.00

I. RNA Editing: General Overview of Underlying Biochemical Mechanisms and Evolutionary Development

RNA editing is defined as a process through which the nucleotide sequence specified in the transcript is different from that in the genomically templated version. From a mechanistic standpoint, it may be viewed as the biochemical equivalent of a somatic mutation that targets nucleotides in RNA instead of DNA. RNA editing in different organisms employs a variety of genetic mechanisms, whose biochemical basis has been elucidated following the development of in vitro editing assays in which synthetic transcripts are incubated in the presence of cell or tissue extracts and changes in the targeted base examined. These technical advances have facilitated a mechanistic understanding of the precise modification in each case as well as the identification, in specific cases, of at least some of the factors involved. For purposes of understanding the underlying mechanisms, RNA editing is divided into two distinct classes, namely insertion-deletion and substitutional (reviewed in Refs. (1,2)). An understanding of these distinct reaction mechanisms illustrates the evolution and complexity of mammalian C to U RNA editing.

A. Insertion-Deletion RNA Editing

Insertion-deletion-type RNA editing was the original example of this form of genetic regulation. This model of transcript editing occurs in mitochondrial RNAs of kinetoplastid species and predominantly involves insertion (or occasional deletion) of varying numbers of uridine (U) residues into the RNA (3). These U insertions or deletions occur mostly within coding regions of mRNA and function to correct transcriptional frameshifts, thereby yielding translatable RNA templates (3). The mechanism involves a series of cleavage-ligation reactions catalyzed by a multicomponent protein complex that is appropriately targeted through base pairing with a guide RNA that permits editing to proceed in a 3' to 5' direction (3). Mitochondrial RNA editing in the slime mold Physarum polycephalum involves cotranscriptional nucleotide insertion, individually or as dinucleotides (CU, CG, GU), in a 5' to 3' direction close to the end of the nascent RNA (1). Insertional RNA-editing activity in mitochondrial extracts copurifies with large transcription elongation complexes (TECs) (4). The efficiency and specificity of insertional RNA editing is modulated by concentration of both the inserted nucleotide and its 5' neighbor as well as temporary pausing of the RNA polymerase component of the TECs, the latter serving to augment recognition of the editing site in the nascent transcript (5).

B. Substitutional RNA Editing

This second model of RNA editing occurs in both plants and mammals. Substitutional RNA editing in plants predominantly involves C to U transitions targeting mitochondrial and chloroplast mRNAs and certain tRNAs (1). In chloroplasts of higher plants approximately 30 editing sites have been described, all C to U and all confined to mRNAs (1). In vitro RNA-editing assays have established that synthetic transcripts containing ~ 30 nucleotides are accurately edited, suggesting that the cis-acting elements are located close to the edited site and are sufficient to support this biochemical modification (1). Although no conserved sequence elements have yet emerged and no consensus secondary structure has been found in these edited transcripts, studies in chloroplasts indicate that the identity of the closest neighboring nucleotide may be critical for editing (6,7). The development of an in vitro assay for chloroplast C to U editing has allowed refinement of the cis-acting requirements and has yielded two candidate genes, a site-specific RNA-binding protein (p25) that binds to a cis-acting element upstream of the edited base and a chloroplast ribonucleoprotein (RNP) (cp31) that may function as an adaptor protein (8). Extensive C to U changes have been proposed to exist in the mitochondrial RNAs of Arabidopsis, where over 6% of all cytosines in the coding region are edited (9), suggesting that RNA editing may be a more widespread mechanism for modifying gene expression than originally suspected.

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