The Kinetochore: (eBook)

From Molecular Discoveries to Cancer Therapy

Peter De Wulf, William Earnshaw (Herausgeber)

eBook Download: PDF

2008 | 2009
XIII, 516 Seiten
Springer New York (Verlag)
978-0-387-69076-6 (ISBN)

Infos

Kinetochores orchestrate the faithful transmission of chromosomes from one generation to the next. Kinetochores were first depicted over 100 years ago, but kinetochore research has progressed by leaps and bounds since the first description of their constituent DNA and proteins in the 1980s. 'The Kinetochore: from Molecular Discoveries to Cancer Therapy' presents a thorough up-to-date analysis of kinetochore and centromere composition, formation, regulation, and activity, both in mitosis and meiosis, in humans and 'model' eukaryotic species, and at natural and mutant neocentromeres. Recently initiated translational research on kinetochores is also discussed as kinetochores are being mined as a very rich target for the next generations of anti-cancer drugs.

---

Kinetochores orchestrate the faithful transmission of chromosomes from one generation to the next. Kinetochores were first depicted over 100 years ago, but kinetochore research has progressed by leaps and bounds since the first description of their constituent DNA and proteins in the 1980s. "e;The Kinetochore: from Molecular Discoveries to Cancer Therapy"e; presents a thorough up-to-date analysis of kinetochore and centromere composition, formation, regulation, and activity, both in mitosis and meiosis, in humans and "e;model"e; eukaryotic species, and at natural and mutant neocentromeres. Recently initiated translational research on kinetochores is also discussed as kinetochores are being mined as a very rich target for the next generations of anti-cancer drugs.

Inhalt

Preface 5
Contents 8
Contributors 10
Centromeres and Kinetochores: An Historical Perspective 13
1.1 Identification of Yeast Centromere DNA 13
1.2 Point Versus Regional Centromeres 19
1.3 Conditional Centromeres, Conditional ARS 20
1.4 Epigenetic Specification of Centromere Function 20
1.5 Centromere Proteins 21
1.6 Organization of Centromere in Chromatin 22
1.7 Centromeres in Living Cells 23
1.8 What is the Minimal Chromosome Segregation Unit? 26
1.9 Future Questions 27
References 27
The Basics of Chromosome Segregation 33
2.1 Scope of this Chapter 33
2.2 Gene Identification in Chromosome Segregation is Incomplete 35
2.3 Basic Versus Quality Control Mechanisms 36
2.4 Gene Nomenclature for Chromosome Segregation 37
2.5 Basic Mutant Phenotypes 38
2.6 Simple Analogies of the Chromosome Segregation Process 39
2.6.1 Cooking Analogy 40
2.6.2 Festival Analogy 40
2.6.3 Freight Train Analogy 40
2.6.4 Glue-Cohesion Analogy 41
2.6.5 Cleansing Analogy 41
2.6.6 Chromosome-Corpse Analogy 42
2.7 Centromere and Kinetochore 42
2.8 Basics of Centromere-Kinetochore Proteins 43
2.9 Generation of Force Required to Segregate Separated Chromatids Towards the Poles 44
2.10 Key Players in Chromosome Segregation 45
2.10.1 CENP-A and Its Recruitment Factors 45
2.10.2 Cohesin for Cohesion, DNA-Break Repair, and Transcriptional Regulation 46
2.10.3 Condensin for Condensation, Segregation, and DNA-Damage Repair 47
2.10.4 Components Required for the Mitotic Checkpoint 48
2.10.5 Components Required for Anaphase 50
2.11 Future Prospects 51
References 51
The Centromere 57
3.1 Introduction 57
3.2 Centromeric DNA: Essential Points and Regional Differences 59
3.2.1 Saccharomyces Cerevisiae 59
3.2.2 Schizosaccharomyces Pombe 61
3.2.3 Candida Albicans 62
3.2.4 Drosophila Melanogaster 62
3.2.5 Plant Centromeres 63
3.2.6 Mouse Centromeres 63
3.2.7 Human Centromeres 64
3.2.8 Caenorhabditis Elegans 65
3.3 Domain Organization of the Centromere 66
3.4 CENP-A, a Variant Histone, is the Foundation of the Kinetochore 68
3.5 CENP-B, a DNA Binding Protein that Positions Centromeric Nucleosomes and Participates in Heterochromatin Assembly 70
3.6 CENP-C, -H, and -I: a Trilogy of Proteins Within the Pre-Kinetochore 72
3.7 Centromeric Chromatin Contains Histone Variants, Core Histone Modifications, and NonHistone Proteins 73
3.8 Centromeres and RNA 76
3.9 Dynamics of CEN Chromatin and Mechanisms for Regulating the Centromere Region 77
3.10 Identification of CENP-A Loading/Interacting Factors 79
3.11 Centromeric Boundaries: Sequence Elements or Regional Boundaries? 79
3.12 Concluding Remarks 80
References 81
Neocentromeres 89
4.1 Introduction 89
4.2 Human Neocentromeres 90
4.2.1 Frequency of Neocentromere Formation in Humans 92
4.3 Centromere Repositioning and Speciation 92
4.4 Protein Studies at Neocentromeres 96
4.4.1 CENP-A 96
4.4.2 CENP-C and CENP-H 100
4.4.3 The Chromosome Scaffold 101
4.4.4 HP1alpha 102
4.5 Gene Expression Within Neocentromeres 102
4.6 Neocentromere Formation 103
4.6.1 Neocentromerisation 103
4.6.2 Neocentromere Hotspots 106
4.6.3 DNA Sequence Similarities 109
4.7 Epigenetic Maintenance of Neocentromeres 110
4.8 Neocentromeres and Cancer 111
4.8.1 Lipomatous Tumours 111
4.8.2 Other Cancers 112
4.9 Conclusion 112
References 113
Human Artificial Centromeres: De novo Assembly of Functional Centromeres on Human Artificial Chromosomes 119
5.1 Introduction 119
5.2 Role of Repetitive Centromeric DNA in Kinetochore Assembly 121
5.3 Epigenetic Mechanisms in Forming a Functional Centromere 123
5.4 Human Artificial Chromosomes 124
5.4.1 Role of Alphoid DNA in De Novo Assembly of Centromeres on Human Artificial Chromosomes 124
5.4.2 Functional Centromeres in Stable HACs 125
5.4.3 The Role of CENP-A Chromatin in Establishing and Maintaining a Functional Human Centromere 126
5.4.4 Assembly and Spreading of CENP-A Chromatin in HACs 128
5.4.5 H3K9me3 Chromatin Formation Inhibits CENP-A Deposition on Transfected 10 kb Alphoid Arrays 129
5.4.6 CENP-B Box Density and Alphoid Length Influence Formation of CENP-A Chromatin 130
5.4.7 A Dynamic Balance Between CENP-A Chromatin and Heterochromatin in Alphoid DNA 130
5.4.8 The Role of Vector Sequences in Heterochromatization and HAC Formation 131
5.4.9 The Role of Heterochromatin in De Novo HAC Formation 133
5.5 Models for Centromere Structure on HACs and Native Chromosomes 135
5.6 Summary 136
References 137
Kinetochore Composition, Formation, and Organization 145
6.1 Organization and Formation of Kinetochores 146
6.2 The Centromeric Sequence does not Define Centromere Identity 147
6.3 Establishing Centromere Identity 150
6.3.1 CENP-A Marks Centromeres 150
6.3.2 Incorporation of CENP-A in Centromeric Nucleosomes 161
6.4 Identification and Characterization of Kinetochore Proteins and Complexes 164
6.4.1 Identification of Vertebrate Kinetochore Proteins 164
6.4.2 Identification of Yeast Kinetochore Proteins 166
6.4.3 Biophysical and Structural Characterization of Kinetochore Proteins and Complexes 168
6.5 Hierarchical Assembly of Kinetochores 169
6.5.1 Inner Components of the Budding Yeast Kinetochore 171
6.5.2 Middle Components of the Budding Yeast Kinetochore 172
6.5.3 Outer Components of the Budding Yeast Kinetochore 173
6.5.4 Constitutively Associated Components in Vertebrate Kinetochores 174
6.5.5 G2-Associating Components in Vertebrate Kinetochores 176
6.5.6 Mitosis-Associated Components in Vertebrate Kinetochores 177
6.5.7 Stable Versus Dynamic Components in Vertebrate Kinetochores 179
6.5.8 Kinetochore Assembly in Other Eukaryotes 181
6.5.9 Kinetochore Assembly in Meiosis 181
6.6 Structural Organization of Kinetochores 185
6.6.1 Structural Organization of Budding Yeast Kinetochores 185
6.6.2 Structural Organization of Vertebrate Kinetochores 187
6.7 Final Comment 187
References 188
Evolution of Centromeres and Kinetochores: A Two-Part Fugue 204
7.1 Centromeric Nucleosomes as Kinetochore Subunits 205
7.2 The Epigenetic and Genetic Nature of Centromeres 206
7.3 Point Centromeres in Budding Yeast 207
7.4 Short Centromeres in Unicellular Eukaryotes 207
7.5 Regional Centromeres 208
7.5.1 Centromeric Satellite Dynamics 210
7.6 Centromere Drive 211
7.6.1 Classical Neocentromeres of Maize 211
7.6.2 Karyotype Evolution 212
7.6.3 The Spindle in Female Meiosis 214
7.6.4 Centromere Repositioning 216
7.7 Evolution of Kinetochore Components 217
7.7.1 Conservation of Kinetochore Components 218
7.7.2 CENP-A/CenH3 Conservation 219
7.7.3 Recurrent Positive Selection in CENP-A/CenH3s 221
7.7.4 CENP-C 223
7.7.5 Ndc80/Hec1 225
7.7.6 Nup 107-160 Complex 225
7.8 Holocentric Chromosomes 226
7.8.1 Caenorhabditis 227
7.8.2 Parascaris 229
7.8.3 Luzula 229
7.9 Origin of the Kinetochore? 231
7.10 Conclusion 232
References 232
Mitotic Spindle Assembly Mechanisms 241
8.1 Introduction 241
8.2 Intrinsic Properties of Microtubules Facilitate Spindle Assembly and Function 242
8.3 Structural Organization of the Mitotic Microtubule Array 243
8.4 Current Models of Spindle Assembly 244
8.5 Microtubule Dynamics Affect Spindle Assembly and Bipolarity 247
8.6 Microtubule-Based Motors Are Critical for Spindle Organization 249
8.7 Non-microtubule Structures in the Spindle 256
8.8 The Spindle Pole 257
8.9 The Role of Chromosomes: Biochemical Signals 259
8.10 The Role of Chromosomes: Microtubule Capture 263
8.11 Modern Approaches to Study Spindle Assembly 263
References 265
Kinetochore-Microtubule Interactions 279
9.1 Introduction 279
9.2 Kinetochore Capture of Microtubules 280
9.2.1 Efficiency of Capture 282
9.2.2 The Role of RanGTP Gradients 282
9.2.3 Kinetochore-Derived Microtubules 283
9.2.4 Kinetochore Transport Sliding vs. Pulling
9.3 The Kinetochore-Microtubule Interface 286
9.4 Bi-Orientation and Congression 288
9.4.1 Role of Tension in Bi-orientation 290
9.4.2 The Chromosomal Passenger Complex (CPC) 291
9.4.3 Mps1 Kinase 293
9.4.4 Congression 294
9.5 Kinetochore Influence on Microtubule Dynamics 294
9.6 Anaphase 295
9.7 Conclusions and Perspectives 296
References 297
Post-Translational Modifications that Regulate Kinetochore Activity 303
10.1 Introduction 303
10.2 The Post-Translational Modifications 304
10.2.1 Phosphorylation 304
10.2.2 Ubiquitylation and Sumoylation 304
10.2.3 Methylation and Acetylation 306
10.2.4 Farnesylation 314
10.2.5 The Dynamic Control of Modifications 314
10.3 The Regulatory Enzymes 315
10.3.1 The Kinases 315
10.3.2 The Phosphatases 319
10.3.3 Ubiquitin and SUMO Enzymes 320
10.3.4 Methyltransferases and Acetyltransferases 322
10.4 Centromere Specification 323
10.4.1 Canonical Histone Modifications at the Centromere 326
10.4.2 The CENP-A Histone Variant 327
10.4.3 The H2A.Z Histone Variant 328
10.4.4 Heterochromatin Modifications 329
10.5 The Regulation of Kinetochore-Microtubule Attachments 330
10.5.1 The Ndc80 Complex 330
10.5.2 The Mtw1/Mis12 Complex 331
10.5.3 The Dam1/DASH/DDD Complex 333
10.5.4 The Budding Yeast CBF3 Complex 334
10.5.5 Microtubule-Associated Proteins 335
10.5.5.1 Plk1-Interacting Checkpoint ‘‘Helicase’’ (PICH) 338
10.6 Summary and Perspectives 339
References 340
The Role of the Kinetochore in Spindle Checkpoint Signaling 354
11.1 Background 354
11.2 The Role of the Kinetochore in Spindle Checkpoint Signaling 357
11.3 Mapping the Spindle Checkpoint Within the Kinetochore in Yeast 358
11.4 Early Lessons from Metazoan Systems 361
11.5 Roles of Protein Kinases in Checkpoint Signaling 363
11.6 Connecting the Signal to Microtubule Attachments 365
11.7 A Model for Kinetochore Regulation of Occupancy Checkpoint Signaling 367
11.8 The Tension Checkpoint and Roles of the CPC 370
11.9 Summary and Future Directions 371
References 372
Kinetochore Regulation of Anaphase and Cytokinesis 380
12.1 Introduction 380
12.1.3 Regulation of Anaphase Events 381
12.1.3 Chromosomal Passengers and Mitosis 384
12.1.3 Chromosomal Passengers Regulate Multiple Mitotic Events 384
12.2 Catalog of Chromosomal Passenger Complexes 387
12.2.1 Core Chromosomal Passengers 387
12.2.2 Non-Core Chromosomal Passengers (The CBF3 and DASH Complexes, and CENP-F) 388
12.3 Kinetochore and Chromosomal Passengers Regulation of Anaphase Mechanics 392
12.3.1 Chromosome Segregation: Metaphase - Anaphase A 392
12.3.2 Spindle Integrity - Anaphase B 393
12.3.3 Cytokinesis 394
12.4 A Model of Chromosomal Passenger Coordination of Anaphase 397
References 398
Roles of Centromeres and Kinetochores in Meiosis 404
13.1 Overview of Meiosis and the Role of the Kinetochore 404
13.2 Centromeres and Cohesin 406
13.2.1 Cohesin Regulation in Mitosis 406
13.2.2 Composition of Meiotic Cohesin 407
13.2.3 Separase is the Trigger for Chromosome Segregation in Meiosis I and Meiosis II 408
13.2.4 Protectors of Centromeric Cohesion 409
13.2.5 Protection of Centromeric Cohesion During Meiosis 410
13.2.6 Protection of Centromeric Cohesion During Mammalian Mitosis 412
13.2.7 Establishment of a Specialized Domain of Cohesin Around the Centromere 413
13.2.8 Establishment of a Protector at the Centromere 415
13.2.9 Switching Off the Protector 419
13.3 Mono-Orientation of Kinetochores 421
13.3.1 Monopolar Attachment is Achieved by Modification of the Kinetochore 421
13.3.2 Monopolin Achieves Monopolar Attachment in Budding Yeast 421
13.3.3 Cohesin is Required for Monopolar Attachment in Other Organisms 425
13.4 Bi-Orientation of Homologues 426
13.4.1 Spindle Assembly Checkpoint in Mitosis 427
13.4.2 The Spindle Checkpoint is Required in Meiosis 427
13.5 Roles of Centromeres in Meiotic Prophase 429
13.6 The Meiotic Kinetochore and Disease 430
References 432
The Kinetochore-Cancer Connection 441
14.1 Introduction 441
14.2 Mitotic Targets Involved in Chromosomal Instability 443
14.3 Kinetochore Dysfunction and Cancer 447
14.4 Clinical Applications 451
References 452
The Kinetochore as Target for Cancer Drug Development 463
15.1 Introduction 463
15.2 The Centromere/Kinetochore Complex 464
15.3 Kinetochore Proteins and Cancer Development 465
15.4 The Strategies: How can Kinetochore Proteins be Used as Drug Targets 466
15.5 Preclinical and Clinical Research on Kinetochore Proteins as Anticancer Drug Targets 469
15.5.1 From Drugs to Kinetochore Proteins 469
15.5.1.1 HSP90 Inhibitors 469
15.5.1.2 Farnesyltransferase Inhibitors (FTIs) 470
15.5.2 From Kinetochore Proteins to Drugs 471
15.5.2.1 Aurora B Kinase 471
15.5.2.2 Plk1 Kinase 473
15.5.2.3 Spindle Checkpoint Proteins 475
15.5.2.4 Other Enzymes: Chk1 and CENP-E 476
15.5.2.5 Other Kinetochore Proteins: Survivin and the HEC1-Nuf2 Complex 478
15.6 Challenges and Future Directions 479
References 481
Index 488

Produkt-Details

• Erscheint lt. Verlag: 16.12.2008
• Zusatzinfo: XIII, 516 p. With 4-page color insert.
• Verlagsort: New York
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Mikrobiologie / Infektologie / Reisemedizin
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Themenwelt: Studium ► 2. Studienabschnitt (Klinik) ► Humangenetik
• Themenwelt: Naturwissenschaften ► Biologie ► Mikrobiologie / Immunologie
• Themenwelt: Naturwissenschaften ► Biologie ► Zellbiologie
• Themenwelt: Technik
• Schlagworte: cell division • Chromosom • cytokinesis • DNA • eukaryotic chromosome • Evolution • Functional Analysis • kinetochores • neocentromeres • Post-translational modification • proteins • Regulation • tissue • Translation • tumorogenesis
• ISBN-10: 0-387-69076-X / 038769076X
• ISBN-13: 978-0-387-69076-6 / 9780387690766