De Wulf / Earnshaw The Kinetochore:

From Molecular Discoveries to Cancer Therapy
1. Auflage 2008
ISBN: 978-0-387-69076-6
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 516 Seiten

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.

Autoren/Hrsg.

De Wulf, Peter

Earnshaw, William

Inhaltsverzeichnis

1;Preface;5
2;Contents;8
3;Contributors;10
4;Centromeres and Kinetochores: An Historical Perspective;13
4.1;1.1 Identification of Yeast Centromere DNA;13
4.2;1.2 Point Versus Regional Centromeres;19
4.3;1.3 Conditional Centromeres, Conditional ARS;20
4.4;1.4 Epigenetic Specification of Centromere Function;20
4.5;1.5 Centromere Proteins;21
4.6;1.6 Organization of Centromere in Chromatin;22
4.7;1.7 Centromeres in Living Cells;23
4.8;1.8 What is the Minimal Chromosome Segregation Unit?;26
4.9;1.9 Future Questions;27
4.10;References;27
5;The Basics of Chromosome Segregation;33
5.1;2.1 Scope of this Chapter;33
5.2;2.2 Gene Identification in Chromosome Segregation is Incomplete;35
5.3;2.3 Basic Versus Quality Control Mechanisms;36
5.4;2.4 Gene Nomenclature for Chromosome Segregation;37
5.5;2.5 Basic Mutant Phenotypes;38
5.6;2.6 Simple Analogies of the Chromosome Segregation Process;39
5.6.1;2.6.1 Cooking Analogy;40
5.6.2;2.6.2 Festival Analogy;40
5.6.3;2.6.3 Freight Train Analogy;40
5.6.4;2.6.4 Glue-Cohesion Analogy;41
5.6.5;2.6.5 Cleansing Analogy;41
5.6.6;2.6.6 Chromosome-Corpse Analogy;42
5.7;2.7 Centromere and Kinetochore;42
5.8;2.8 Basics of Centromere-Kinetochore Proteins;43
5.9;2.9 Generation of Force Required to Segregate Separated Chromatids Towards the Poles;44
5.10;2.10 Key Players in Chromosome Segregation;45
5.10.1;2.10.1 CENP-A and Its Recruitment Factors;45
5.10.2;2.10.2 Cohesin for Cohesion, DNA-Break Repair, and Transcriptional Regulation;46
5.10.3;2.10.3 Condensin for Condensation, Segregation, and DNA-Damage Repair;47
5.10.4;2.10.4 Components Required for the Mitotic Checkpoint;48
5.10.5;2.10.5 Components Required for Anaphase;50
5.11;2.11 Future Prospects;51
5.12;References;51
6;The Centromere;57
6.1;3.1 Introduction;57
6.2;3.2 Centromeric DNA: Essential Points and Regional Differences;59
6.2.1;3.2.1 Saccharomyces Cerevisiae;59
6.2.2;3.2.2 Schizosaccharomyces Pombe;61
6.2.3;3.2.3 Candida Albicans;62
6.2.4;3.2.4 Drosophila Melanogaster;62
6.2.5;3.2.5 Plant Centromeres;63
6.2.6;3.2.6 Mouse Centromeres;63
6.2.7;3.2.7 Human Centromeres;64
6.2.8;3.2.8 Caenorhabditis Elegans;65
6.3;3.3 Domain Organization of the Centromere;66
6.4;3.4 CENP-A, a Variant Histone, is the Foundation of the Kinetochore;68
6.5;3.5 CENP-B, a DNA Binding Protein that Positions Centromeric Nucleosomes and Participates in Heterochromatin Assembly;70
6.6;3.6 CENP-C, -H, and -I: a Trilogy of Proteins Within the Pre-Kinetochore;72
6.7;3.7 Centromeric Chromatin Contains Histone Variants, Core Histone Modifications, and NonHistone Proteins;73
6.8;3.8 Centromeres and RNA;76
6.9;3.9 Dynamics of CEN Chromatin and Mechanisms for Regulating the Centromere Region;77
6.10;3.10 Identification of CENP-A Loading/Interacting Factors;79
6.11;3.11 Centromeric Boundaries: Sequence Elements or Regional Boundaries?;79
6.12;3.12 Concluding Remarks;80
6.13;References;81
7;Neocentromeres;89
7.1;4.1 Introduction;89
7.2;4.2 Human Neocentromeres;90
7.2.1;4.2.1 Frequency of Neocentromere Formation in Humans;92
7.3;4.3 Centromere Repositioning and Speciation;92
7.4;4.4 Protein Studies at Neocentromeres;96
7.4.1;4.4.1 CENP-A;96
7.4.2;4.4.2 CENP-C and CENP-H;100
7.4.3;4.4.3 The Chromosome Scaffold;101
7.4.4;4.4.4 HP1alpha;102
7.5;4.5 Gene Expression Within Neocentromeres;102
7.6;4.6 Neocentromere Formation;103
7.6.1;4.6.1 Neocentromerisation;103
7.6.2;4.6.2 Neocentromere Hotspots;106
7.6.3;4.6.3 DNA Sequence Similarities;109
7.7;4.7 Epigenetic Maintenance of Neocentromeres;110
7.8;4.8 Neocentromeres and Cancer;111
7.8.1;4.8.1 Lipomatous Tumours;111
7.8.2;4.8.2 Other Cancers;112
7.9;4.9 Conclusion;112
7.10;References;113
8;Human Artificial Centromeres: De novo Assembly of Functional Centromeres on Human Artificial Chromosomes;119
8.1;5.1 Introduction;119
8.2;5.2 Role of Repetitive Centromeric DNA in Kinetochore Assembly;121
8.3;5.3 Epigenetic Mechanisms in Forming a Functional Centromere;123
8.4;5.4 Human Artificial Chromosomes;124
8.4.1;5.4.1 Role of Alphoid DNA in De Novo Assembly of Centromeres on Human Artificial Chromosomes;124
8.4.2;5.4.2 Functional Centromeres in Stable HACs;125
8.4.3;5.4.3 The Role of CENP-A Chromatin in Establishing and Maintaining a Functional Human Centromere;126
8.4.4;5.4.4 Assembly and Spreading of CENP-A Chromatin in HACs;128
8.4.5;5.4.5 H3K9me3 Chromatin Formation Inhibits CENP-A Deposition on Transfected 10 kb Alphoid Arrays;129
8.4.6;5.4.6 CENP-B Box Density and Alphoid Length Influence Formation of CENP-A Chromatin;130
8.4.7;5.4.7 A Dynamic Balance Between CENP-A Chromatin and Heterochromatin in Alphoid DNA;130
8.4.8;5.4.8 The Role of Vector Sequences in Heterochromatization and HAC Formation;131
8.4.9;5.4.9 The Role of Heterochromatin in De Novo HAC Formation;133
8.5;5.5 Models for Centromere Structure on HACs and Native Chromosomes;135
8.6;5.6 Summary;136
8.7;References;137
9;Kinetochore Composition, Formation, and Organization;145
9.1;6.1 Organization and Formation of Kinetochores;146
9.2;6.2 The Centromeric Sequence does not Define Centromere Identity;147
9.3;6.3 Establishing Centromere Identity;150
9.3.1;6.3.1 CENP-A Marks Centromeres;150
9.3.2;6.3.2 Incorporation of CENP-A in Centromeric Nucleosomes;161
9.4;6.4 Identification and Characterization of Kinetochore Proteins and Complexes;164
9.4.1;6.4.1 Identification of Vertebrate Kinetochore Proteins;164
9.4.2;6.4.2 Identification of Yeast Kinetochore Proteins;166
9.4.3;6.4.3 Biophysical and Structural Characterization of Kinetochore Proteins and Complexes;168
9.5;6.5 Hierarchical Assembly of Kinetochores;169
9.5.1;6.5.1 Inner Components of the Budding Yeast Kinetochore;171
9.5.2;6.5.2 Middle Components of the Budding Yeast Kinetochore;172
9.5.3;6.5.3 Outer Components of the Budding Yeast Kinetochore;173
9.5.4;6.5.4 Constitutively Associated Components in Vertebrate Kinetochores;174
9.5.5;6.5.5 G2-Associating Components in Vertebrate Kinetochores;176
9.5.6;6.5.6 Mitosis-Associated Components in Vertebrate Kinetochores;177
9.5.7;6.5.7 Stable Versus Dynamic Components in Vertebrate Kinetochores;179
9.5.8;6.5.8 Kinetochore Assembly in Other Eukaryotes;181
9.5.9;6.5.9 Kinetochore Assembly in Meiosis;181
9.6;6.6 Structural Organization of Kinetochores;185
9.6.1;6.6.1 Structural Organization of Budding Yeast Kinetochores;185
9.6.2;6.6.2 Structural Organization of Vertebrate Kinetochores;187
9.7;6.7 Final Comment;187
9.8;References;188
10;Evolution of Centromeres and Kinetochores: A Two-Part Fugue;204
10.1;7.1 Centromeric Nucleosomes as Kinetochore Subunits;205
10.2;7.2 The Epigenetic and Genetic Nature of Centromeres;206
10.3;7.3 Point Centromeres in Budding Yeast;207
10.4;7.4 Short Centromeres in Unicellular Eukaryotes;207
10.5;7.5 Regional Centromeres;208
10.5.1;7.5.1 Centromeric Satellite Dynamics;210
10.6;7.6 Centromere Drive;211
10.6.1;7.6.1 Classical Neocentromeres of Maize;211
10.6.2;7.6.2 Karyotype Evolution;212
10.6.3;7.6.3 The Spindle in Female Meiosis;214
10.6.4;7.6.4 Centromere Repositioning;216
10.7;7.7 Evolution of Kinetochore Components;217
10.7.1;7.7.1 Conservation of Kinetochore Components;218
10.7.2;7.7.2 CENP-A/CenH3 Conservation;219
10.7.3;7.7.3 Recurrent Positive Selection in CENP-A/CenH3s;221
10.7.4;7.7.4 CENP-C;223
10.7.5;7.7.5 Ndc80/Hec1;225
10.7.6;7.7.6 Nup 107-160 Complex;225
10.8;7.8 Holocentric Chromosomes;226
10.8.1;7.8.1 Caenorhabditis;227
10.8.2;7.8.2 Parascaris;229
10.8.3;7.8.3 Luzula;229
10.9;7.9 Origin of the Kinetochore?;231
10.10;7.10 Conclusion;232
10.11;References;232
11;Mitotic Spindle Assembly Mechanisms;241
11.1;8.1 Introduction;241
11.2;8.2 Intrinsic Properties of Microtubules Facilitate Spindle Assembly and Function;242
11.3;8.3 Structural Organization of the Mitotic Microtubule Array;243
11.4;8.4 Current Models of Spindle Assembly;244
11.5;8.5 Microtubule Dynamics Affect Spindle Assembly and Bipolarity;247
11.6;8.6 Microtubule-Based Motors Are Critical for Spindle Organization;249
11.7;8.7 Non-microtubule Structures in the Spindle;256
11.8;8.8 The Spindle Pole;257
11.9;8.9 The Role of Chromosomes: Biochemical Signals;259
11.10;8.10 The Role of Chromosomes: Microtubule Capture;263
11.11;8.11 Modern Approaches to Study Spindle Assembly;263
11.12;References;265
12;Kinetochore-Microtubule Interactions;279
12.1;9.1 Introduction;279
12.2;9.2 Kinetochore Capture of Microtubules;280
12.2.1;9.2.1 Efficiency of Capture;282
12.2.2;9.2.2 The Role of RanGTP Gradients;282
12.2.3;9.2.3 Kinetochore-Derived Microtubules;283
12.2.4;9.2.4 Kinetochore Transport; Sliding vs. Pulling;284
12.3;9.3 The Kinetochore-Microtubule Interface;286
12.4;9.4 Bi-Orientation and Congression;288
12.4.1;9.4.1 Role of Tension in Bi-orientation;290
12.4.2;9.4.2 The Chromosomal Passenger Complex (CPC);291
12.4.3;9.4.3 Mps1 Kinase;293
12.4.4;9.4.4 Congression;294
12.5;9.5 Kinetochore Influence on Microtubule Dynamics;294
12.6;9.6 Anaphase;295
12.7;9.7 Conclusions and Perspectives;296
12.8;References;297
13;Post-Translational Modifications that Regulate Kinetochore Activity;303
13.1;10.1 Introduction;303
13.2;10.2 The Post-Translational Modifications;304
13.2.1;10.2.1 Phosphorylation;304
13.2.2;10.2.2 Ubiquitylation and Sumoylation;304
13.2.3;10.2.3 Methylation and Acetylation;306
13.2.4;10.2.4 Farnesylation;314
13.2.5;10.2.5 The Dynamic Control of Modifications;314
13.3;10.3 The Regulatory Enzymes;315
13.3.1;10.3.1 The Kinases;315
13.3.2;10.3.2 The Phosphatases;319
13.3.3;10.3.3 Ubiquitin and SUMO Enzymes;320
13.3.4;10.3.4 Methyltransferases and Acetyltransferases;322
13.4;10.4 Centromere Specification;323
13.4.1;10.4.1 Canonical Histone Modifications at the Centromere;326
13.4.2;10.4.2 The CENP-A Histone Variant;327
13.4.3;10.4.3 The H2A.Z Histone Variant;328
13.4.4;10.4.4 Heterochromatin Modifications;329
13.5;10.5 The Regulation of Kinetochore-Microtubule Attachments;330
13.5.1;10.5.1 The Ndc80 Complex;330
13.5.2;10.5.2 The Mtw1/Mis12 Complex;331
13.5.3;10.5.3 The Dam1/DASH/DDD Complex;333
13.5.4;10.5.4 The Budding Yeast CBF3 Complex;334
13.5.5;10.5.5 Microtubule-Associated Proteins;335
13.5.5.1;10.5.5.1 Plk1-Interacting Checkpoint ‘‘Helicase’’ (PICH);338
13.6;10.6 Summary and Perspectives;339
13.7;References;340
14;The Role of the Kinetochore in Spindle Checkpoint Signaling;354
14.1;11.1 Background;354
14.2;11.2 The Role of the Kinetochore in Spindle Checkpoint Signaling;357
14.3;11.3 Mapping the Spindle Checkpoint Within the Kinetochore in Yeast;358
14.4;11.4 Early Lessons from Metazoan Systems;361
14.5;11.5 Roles of Protein Kinases in Checkpoint Signaling;363
14.6;11.6 Connecting the Signal to Microtubule Attachments;365
14.7;11.7 A Model for Kinetochore Regulation of Occupancy Checkpoint Signaling;367
14.8;11.8 The Tension Checkpoint and Roles of the CPC;370
14.9;11.9 Summary and Future Directions;371
14.10;References;372
15;Kinetochore Regulation of Anaphase and Cytokinesis;380
15.1;12.1 Introduction;380
15.1.1;12.1.3 Regulation of Anaphase Events;381
15.1.2;12.1.3 Chromosomal Passengers and Mitosis;384
15.1.3;12.1.3 Chromosomal Passengers Regulate Multiple Mitotic Events;384
15.2;12.2 Catalog of Chromosomal Passenger Complexes;387
15.2.1;12.2.1 Core Chromosomal Passengers;387
15.2.2;12.2.2 Non-Core Chromosomal Passengers (The CBF3 and DASH Complexes, and CENP-F);388
15.3;12.3 Kinetochore and Chromosomal Passengers Regulation of Anaphase Mechanics;392
15.3.1;12.3.1 Chromosome Segregation: Metaphase - Anaphase A;392
15.3.2;12.3.2 Spindle Integrity - Anaphase B;393
15.3.3;12.3.3 Cytokinesis;394
15.4;12.4 A Model of Chromosomal Passenger Coordination of Anaphase;397
15.5;References;398
16;Roles of Centromeres and Kinetochores in Meiosis;404
16.1;13.1 Overview of Meiosis and the Role of the Kinetochore;404
16.2;13.2 Centromeres and Cohesin;406
16.2.1;13.2.1 Cohesin Regulation in Mitosis;406
16.2.2;13.2.2 Composition of Meiotic Cohesin;407
16.2.3;13.2.3 Separase is the Trigger for Chromosome Segregation in Meiosis I and Meiosis II;408
16.2.4;13.2.4 Protectors of Centromeric Cohesion;409
16.2.5;13.2.5 Protection of Centromeric Cohesion During Meiosis;410
16.2.6;13.2.6 Protection of Centromeric Cohesion During Mammalian Mitosis;412
16.2.7;13.2.7 Establishment of a Specialized Domain of Cohesin Around the Centromere;413
16.2.8;13.2.8 Establishment of a Protector at the Centromere;415
16.2.9;13.2.9 Switching Off the Protector;419
16.3;13.3 Mono-Orientation of Kinetochores;421
16.3.1;13.3.1 Monopolar Attachment is Achieved by Modification of the Kinetochore;421
16.3.2;13.3.2 Monopolin Achieves Monopolar Attachment in Budding Yeast;421
16.3.3;13.3.3 Cohesin is Required for Monopolar Attachment in Other Organisms;425
16.4;13.4 Bi-Orientation of Homologues;426
16.4.1;13.4.1 Spindle Assembly Checkpoint in Mitosis;427
16.4.2;13.4.2 The Spindle Checkpoint is Required in Meiosis;427
16.5;13.5 Roles of Centromeres in Meiotic Prophase;429
16.6;13.6 The Meiotic Kinetochore and Disease;430
16.7;References;432
17;The Kinetochore-Cancer Connection;441
17.1;14.1 Introduction;441
17.2;14.2 Mitotic Targets Involved in Chromosomal Instability;443
17.3;14.3 Kinetochore Dysfunction and Cancer;447
17.4;14.4 Clinical Applications;451
17.5;References;452
18;The Kinetochore as Target for Cancer Drug Development;463
18.1;15.1 Introduction;463
18.2;15.2 The Centromere/Kinetochore Complex;464
18.3;15.3 Kinetochore Proteins and Cancer Development;465
18.4;15.4 The Strategies: How can Kinetochore Proteins be Used as Drug Targets;466
18.5;15.5 Preclinical and Clinical Research on Kinetochore Proteins as Anticancer Drug Targets;469
18.5.1;15.5.1 From Drugs to Kinetochore Proteins;469
18.5.1.1;15.5.1.1 HSP90 Inhibitors;469
18.5.1.2;15.5.1.2 Farnesyltransferase Inhibitors (FTIs);470
18.5.2;15.5.2 From Kinetochore Proteins to Drugs;471
18.5.2.1;15.5.2.1 Aurora B Kinase;471
18.5.2.2;15.5.2.2 Plk1 Kinase;473
18.5.2.3;15.5.2.3 Spindle Checkpoint Proteins;475
18.5.2.4;15.5.2.4 Other Enzymes: Chk1 and CENP-E;476
18.5.2.5;15.5.2.5 Other Kinetochore Proteins: Survivin and the HEC1-Nuf2 Complex;478
18.6;15.6 Challenges and Future Directions;479
18.7;References;481
19;Index;488