Contents in Detail
Chapter 1 Genomes 1
Genome Composition 2
DNA 2
Composition Of DNA 3
DNA Structure 4
Primary Structure 4
Secondary Structure 5
Tertiary Structure 9
Superhelicity 10
Superhelicity Generated By Nucleosome Assembly 11
Superhelicity Generated By DNA Gyrases 11
Superhelicity Generated By Transcription 12
Superhelicity Generated By Replication 12
Noncanonical DNA Structures 13
Z-DNA 13
Cruciform DNA 13
Triplex DNA 15
Quadruplex DNA 17
Slipped-Strand DNA 19
Genome Characteristics 19
Chromosome Shape, Number, And Distribution 19
DNA Length 20
C-Value Paradox 20
Genetic Complexity Paradox 22
Summary 23
Additional Reading 25
Literature Cited 25
Chapter 2 Three Domains of Life 27
In the Beginning … 27
Prebiotic Era 28
Cellular Life 30
Phylogenetics 30
Characteristics of the Three Domains 33
Bacteria 34
Archaea 34
Eukaryotes 35
Viruses: Ubiquitous Parasites 37
Summary 37
Additional Reading 37
Chapter 3 Replication Forks 39
DNA Replication 39
Semi-Conservative DNA Replication 40
DNA Replication And Natural Selection 42
DNA Replication Forks 43
The Replication-Fork Paradox 43
Sequence of Events at Replication Forks 46
DNA Unwinding And Leading-Strand Synthesis 47
DNA Relaxation 49
Lagging-Strand Synthesis 50
Conservation Of Replication-Fork Events 53
Organization of Replication Forks 54
Replication-Fork Configuration 54
Replication-Fork Factories 56
Replication-Fork Velocity 58
Nucleotide Pools 59
Summary 61
Additional Reading 62
Literature Cited 62
Chapter 4 Replication Proteins: Leading-Strand Synthesis 63
DNA Helicases 63
The DnaB Family Of Helicases 65
The MCM Family Of Helicases 66
Rotary Engine Activity Of DNA Helicases 67
How Helicases Unwind DNA 68
Single-Strand-Specific DNA-Binding Proteins70
DNA Polymerases 73
The DNA Polymerase I Paradigm 74
DNA Polymerase Families 76
DNA Polymerase Fidelity And Molecular Evolution 83
Sliding Clamps 84
Bacteria 84
Archaea And Eukarya 85
DNA Topoisomerases 85
Type IA Enzymes 86
Type IB Enzymes 87
Type II Enzymes 88
Summary 90
Additional Reading 91
Literature Cited 92
Chapter 5 Replication Proteins: Laggin-Strand Synthesis 93
RNA-Primed Nascent DNA 93
DNA Primase 96XI
Initiation of Okazaki-Fragment Synthesis 98
The Helicase-Primase Paradox 99
Bacteria 100
Archaea And Eukarya100
Handp-off From Primase to Polymerase 101
Bacteria 101
Eukarya 102
Hand-Off From Iniator Polymerase to Replicator Polymerase 102
Sliding Clamp Loaders 103
Bacteria 103
Archaea And Eukarya 104
Primer Excision 105
Bacteria 105Eukarya 106
DNA Ligation 107
THE Ringmaster 109
Dynamic Processivity 111
Summary 114
Additional Reading 115
Chapter 6 Termination 117
Replication-Fork Termination 117
When Forks Collide 117
Topological Problems Unique To Replication-Fork Termination 118
Replication-Fork Barriers 120
Replication-Fork Barriers In Bacteria 120
Replication-Fork Barriers In Eukarya 124
Other Impediments to Replication Forks 126
The Role of Replication-Fork Barriers in Nature 127
The Termination Paradox 127
Protein-Nucleotide Primers 128
Circularization 128
Concatemer Formation 128
Telomeres And Telomerase 128
Summary 133
Additional Reading 134
Chapter 7 Chromatin Assembly, Cohesion, and Modification 135
Chromatin 136
Bacteria 136
Archaea 140
Eukarya 142
Eukaryotic Chromatin and DNA Replication 147
Replication Origins 147
Replication Forks 148
Sister Chromatid Cohesion 154
Formation Of A Cohesin Ring Around Sister Chromatids 155
Establishment Of Cohesion Between Sister Chromatids 157
Dissolution Of Cohesion Between Sister Chromatids 158
Duplication of Epigenetic Information 159
Nucleosome Segregation and Positioning 159
Protein Modification 161
DNA Methylation 163
Summary 166
Additional Reading 167
Literature Cited 167
Chapter 8 Replicons 169
The Replicon Model 169
The Classical Replicon Model 169
The Replicon Model Today 170
Visualizing Replicons 171
Why Replicons? 174
Replicon Taxonomy 175
DNA Structure And Replicator Location 175
Modes Of DNA Replication 176
Modes Of DNA Synthesis 176
Six Manifestations of the Replicon 178
A. dsDNA With Internal Replicators That Use Replication Forks 178
B. dsDNA With Internal Replicators That Use Single-Strand Displacement 179
C. dsDNA With Internal Replicators That Use The Rolling Circle 181
D. dsDNA With Terminal Replicators That Use Single-Strand Displacement And Then Gap-Filling 182
E. ssDNA With Internal Replicators That Use Gap-Filling And Then Single-Strand Displacement 183
F. ssDNA With Terminal Replicators That Use Gap-Filling And Then Single-Strand Displacement 185
Summary 188
Additional Reading 189
Literature Cited 189
Chapter 9 Replication Origins 191
Patterns of Initiation 192
Finding Replication Origins 193
Replicator Activity 193
Origins Of Bidirectional Replication 194
Nascent-Strand Abundance 194xii CONTENTS IN DETAIL
DNA Sequence Duplication 194
Leading-Strand Sequence Bias 195
Characteristics of Replication Origins 195
Origin Anatomy 195
Origin Specificity 197
Origin Function 197
Origin Density 202
Origin Usage 204
Origin Timing 205
Developmental Acquisition of Site-Specificity 206
Paradoxes and Solutions 207
The Replicator Paradox 207
The Site-Selection Paradox 213
The MCM Paradox 215
Summary 218
Additional Reading 221
Literature Cited 222
Chapter 10 Origin Paradigms 223
DNA-Nicking Mechanism 223
Protein-Priming Mechanism 224
DNA Transcription Mechanism 227
Bacteriophage T7 227
Bacteriophage T4 229
Bacterial Plasmid ColE1 229
Mitochondrial DNA 230
DNA Helicase Mechanism 232
Simian Virus 40 232
Polyomavirus 234
Papillomavirus 234
Herpes Simplex Virus 234
DNA Helicase Loader Mechanism 235
Bacteria 236
Archaea 240
Single-Cell Eukarya 242
Multicellular Eukarya 246
Why DNA Helicase Loaders? 254
Amplification Origins 255
Sciara coprophila 255
Drosophila melanogaster 255
Tetrahymena thermophila 258
Summary 259
Chapter 11 Initiation 261
The Road to Replication Forks 262
Replication-Fork Assembly And Cell Proliferation 264
Where The Road Splits 266
Viral Genomes 267
Bacterial Genomes 269
preRC Assembly On Bacterial Genomes 270
preIC Assembly On Bacterial Genomes 272
Archaeal Genomes 273
Eukaryal Genomes 275
preRC Assembly (Origin Licensing) On Eukaryotic Genomes 275
preIC Assembly On Eukaryotic Genomes 281
Summary 285
Additional Reading 286
Literature Cited 286
Chapter 12 Cell Cycles 287
The Bacterial Cell Cycle 287
The Initiator/Replicator Ratio Triggers Genome Duplication 289
Suppression of Reinitiation Within A Single Cell Cycle 290
The Archaeal Cell Cycle 293
The Eukaryotic Mitotic Cell Cycle 293
Common Features 293
Abbreviated Mitotic Cell Cycles 295
Cell-Cycle Analysis 295
Accelerators And Brakes 298
Yin And Yang 301
Genome Duplication Preceds Cell Division 302
Driving the G2ÆM Transition 303
Regulating preRC Assembly 304
Driving The MÆG1 Transition 305
Driving The G1ÆS Transition 307
Preventing DNA Re-Replication 309
Single-Cell Eukarya 310
Multicellular Eukarya 311
Parallel Pathways 315
Functional Redundancy 316
Developmentally Programmed Polyploidy 316
Initiating Endocycles 318
Sustaining Endocycles 321
Two APCs, Two Cell Cycles 322
Summary 322
Additional Reading 324
Chapter 13 Checkpoints 325
Restriction Checkpoint 328
Bacteria 328
Archaea 330
Eukarya 330xiii CONTENTS IN DETAIL
DNA Damage Response 335
The SOS Response In Bacteria 337
Restarting Replication Forks In Bacteria 340
Archaea 346
Eukarya 346
G1 DNA Damage Checkpoint 349
DNA-Replication Checkpoint 350
G2 DNA Damage Checkpoint 353
The Eukaryotic Replisome Revisited 354
Stabilization Of Replication Forks 355
Mediators 357
Replication-Fork Restart In Eukarya 357
G2 Checkpoint 358
Bacteria 359
ukarya 359
Spindle-Assembly Checkpoint 360
Mitotic Cells 360
Meiotic Cells 362
Summary 364
Additional Reading 366
Literature Cited 366
Chapter 14 Human Disease 367
Infectious Diseases 368
Viruses 368
Bacteria 373
Archaea 373
Noninfectious Diseases 374
The Road To Cancer 374
DNA Replication Proteins As Cancer Biomarkers 380
Heritable Diseases 382
The ‘Seven Deadly Sins’ Of DNA Replication 382
The Road To Nucleotide-Repeat Disorders 384
Mutations In DNA Replication Genes 389
Pharmacological Agents That Target DNA Replication 391
Antiviral Pharmaceuticals 391
Antibiotic Pharmaceuticals 396
Anti-Cancer Pharmaceuticals 397
Summary 406
Additional Reading Literature Cited 408
Chapter 15 Evolution of Cellular Replication Machines 409
Replication Machines in Bacteria, Archaea, and Eukarya 409
Making the Jump from RNA to DNA Genomes 411
A Role of Viruses in the Evolution of DNA Genomes? 412
Did DNA Evolve in Viruses as a Way to Evade Host Defenses? 412
Replicon Takeover 414
The Acquisition of Multiple Replication Origins 415
Viruses as a Fossil Record 416
Summary 416
Additional Reading 417
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