Telomeres and Telomerase in Aging, Disease, and Cancer (eBook)

Contents 5
Contributors 7
Introduction 10
1.1 Ageing 10
2.1 Stem Cells 11
3.1 Cancer 12
4.1 Therapies 12
Telomere Shortening and Ageing 14
Cellular versus Organismal Aging 15
1 Cellular Aging: The Hayflick Limit 15
2 Cellular Aging: The End Replication Problem 16
3 Telomeres and Telomerase: A Brief Introduction 17
4 Telomere Shortening and Cellular Aging 19
5 Organismal Aging and Survival 21
5.1 Telomeres and Organismal Aging 21
5.2 Genome Integrity/DNA Damage Response in Postmitotic Aging 23
5.3 Genetic Pathways of Postmitotic Cell and Organismal Survival 24
6 Perspectives 29
References 29
Telomere-Induced Senescence of Primary Cells 35
1 Primary Human Cells and Replicative Senescence 36
2 The Telomere Hypothesis of Cell Aging and Immortalization 39
3 Validation of the Hypothesis 40
4 Exceptions to the Hypothesis 43
5 Mechanism of Telomere-Induced Senescence 45
6 Telomere-Induced Replicative Senescence and Organismal Aging 48
References 50
Telomeres, Senescence, Oxidative Stress, and Heterogeneity 55
1 Heterogeneity: The Hallmark of Ageing 55
2 Replicative Senescence and the Telomere Hypothesis 56
3 Heterogeneity in Senescence 57
4 Heterogeneity and Telomeres 58
5 Heterogeneity and Mitochondria 60
6 Mitochondrial Dysfunction Causes Telomere Dysfunction and Thus Heterogeneity in Replicative Senescence 61
7 Complexities Beyond 64
References 64
Initiation of Genomic Instability, Cellular Senescence, and Organismal Aging by Dysfunctional Telomeres 69
1 Telomeres and Telomerase 69
2 A Six-Protein Core Complex Mediates Telomere End Protection 71
3 Telomere Dysfunction Results in Genomic Instability 72
4 Telomere Dysfunction Initiates p53-Dependent Replicative Senescence 73
5 Consequences of Telomerase Loss In Vivo: The Telomerase Knockout Mouse 74
6 Telomere Shortening and Organismal Aging 76
7 The mTerc-/- Wrn-/- Compound Mutant Mouse as a Model of Human Werner Syndrome 78
8 Conclusions 81
References 82
Telomerase Mutations and Premature Ageing in Humans 88
1 Introduction 89
2 Telomerase and Ageing 89
3 Dyskeratosis Congenita as a Premature Ageing Syndrome 90
3.1 Clinical Presentation of Dyskeratosis Congenita 91
3.2 Similarities and Differences Between DC and Ageing 92
4 Dyskeratosis Congenita and Telomerase Mutations 93
4.1 X-linked DC and Mutations in DKC1 93
4.2 AD DC and Mutations in TERC and TERT 98
4.3 AR DC and Mutations in Other Components 107
5 Telomerase and Cancer 108
6 Conclusion 110
References 110
Telomerase, Telomeres, and Stem Cell Aging 119
Mechanisms of Stem Cell Ageing 120
1 Introduction 120
2 Cell Intrinsic Regulation of HSCs 121
2.1 HSC Cell Cycle Status 122
2.2 HSC Gene Expression Profiles: Transcription Factors and Epigenetic Modification 122
2.3 Maintaining the HSC Population: Stem Cells Make Life or Death Decisions 124
3 Cell-Intrinsic Mechanisms of Stem Cell Dysfunction 125
3.1 Signaling Pathways Implicated in Cell-Intrinsic HSC Ageing 125
3.2 HSC-Intrinsic Mechanisms of Functional Decline Lead to Changes in Stem Cell Number with Age 126
4 Hematopoietic Stem Cell Niches – Extrinsic Regulation of HSCs 129
4.1 The Vascular Niche 129
4.2 The Endosteal Niche 129
4.3 Why Two Stem Cell Niches? 130
4.4 Molecular Interactions within the Niche 130
5 Evaluating Stem Cell–Microenvironment Interactions: Transplantation and Mobilization 133
5.1 Transplantation 134
5.2 Molecular Mechanisms of HSC Homing 134
5.3 Mechanisms of HSC Mobilization 135
6 Functional Changes with Age that Involve both HSCs and the Microenvironment 136
6.1 Effects of Ageing on the Niche 136
6.2 Age-Dependent Lineage Skewing of HSCs 136
6.3 Ageing, Migration, and Nonhematopoietic Tissue Recruitment of HSCs 139
7 Stem Cells and Cancer 140
7.1 HSCs, Cancer Stem Cells, and their Niches 140
7.2 HSCs and Metastatic Cancer Stem Cells use Similar Pathways for Migration 141
8 Conclusion 142
References 142
Senescence Signatures of Human Hematopoietic Stem Cells 150
1 Introduction 150
2 Telomerase Activity in Human HSCs 151
3 Telomere Dynamics in Human HSCs 152
4 Telomere Dynamics in Mature Hematopoietic Cells 153
5 Telomere Manipulation in Adult Stem Cells 155
6 Consequences of Telomerase Inhibition in HSCs 156
7 Lessons from Mice 158
8 Other Factors Determining Self-Renewal and Aging in HSCs 159
9 Conclusions and Outlook 160
References 161
Telomere Shortening Induces Cell Intrinsic Checkpoints and Environmental Alterations Limiting Adult Stem Cell Function 169
1 Telomere Shortening and Replicative Ageing 169
2 Telomere Shortening and Stem Cell Ageing 171
3 Cell Intrinsic Checkpoints in Response to Dysfunctional Telomeres 172
3.1 Atm 174
3.2 p53 174
3.3 p21 176
3.4 Ink4a/Arf 178
3.5 p18, p15, p27, p57 178
4 Telomere Dysfunction Induces Environmental Alterations Limiting Stem Cell Function and Engraftment 178
4.1 Telomere Dysfunction and the Microenvironment 181
5 Outlook 182
References 182
p16INK4a and Stem Cell Ageing: A Telomere- Independent Process? 189
1 Properties of Self-Renewal Relevant to Molecular Ageing 189
2 Stem Cell Function Declines with Ageing 192
2.1 Hematopoietic Stem Cell Ageing 193
2.2 Ageing in Other Tissue-Specific Stem Cells 194
3 Activation of p16INK4a Contributes to Stem Cell Ageing 195
3.1 Senescence and p16INK4a Expression with Ageing 196
3.2 Murine Studies of p16INK4a and Ageing 197
3.3 Human Genomic Studies of p16INK4a and Age- Associated Phenotypes 199
4 What Induces p16INK4a with Ageing? 201
4.1 Polycomb Group Complexes 202
4.2 p16INK4a induction with Ageing: Telomere-Independent? 203
5 Conclusions 203
References 204
Telomerase as a Potential Regulator of Tissue Progenitor Cells 211
1 Telomerase Is Expressed in Tissue Progenitor Cells in Mouse and Human 211
2 TERT Overexpression Causes Progenitor Cells to Proliferate 213
References 216
Telomeres, DNA Damage and Cancer 219
Telomere Shortening and Telomerase Activation during Cancer Formation 220
1 Telomere Shortening and Telomerase Activation Characterize Human Tumorigenesis 220
2 Telomere Shortening Increases Tumor Initiation but Suppresses Tumor Progression in Telomerase- Deficient Mice 223
3 Molecular Mechanisms of Tumor Initiation in Response to Telomere Shortening 224
3 Molecular Mechanisms of Tumor Suppression in Response to Telomere Shortening 226
5 Molecular Mechanisms Promoting Progression of Telomere- Dysfunctional Tumors 228
6 Conclusions 231
References 231
Telomere Binding Proteins and Disease 236
1 Chromatin Structure of Mammalian Telomeres 236
1.1 Telomeric DNA 236
1.2 Telomere Repeat Binding Factors 237
1.3 Histone Modifications at Mammalian Telomeres 238
1.4 DNA Methylation at Mammalian Subtelomeres 239
2 Telomere Maintenance Mechanisms in Mammals 240
2.1 Telomerase 240
2.2 Alternative Lengthening of Telomeres (ALT) 240
2.3 Epigenetic Regulation of Telomere Length and Telomere Recombination 241
3 Role of Mammalian Telomeres in Disease 242
3.1 The Telomerase-Deficient Mouse Model 242
3.2 Role of Telomere Length and Telomerase in Human Disease 244
3.3 Role of Telomere-Binding Proteins in Disease 245
References 247
Therapeutic Targets 252
Targeting Telomerase: Therapeutic Options for Cancer Treatment 253
1 Target-Based Drug Discovery and Telomerase Validation 253
2 Telomerase-Specific Adaptive Immunotherapy 256
2.1 Rationale 256
2.2 Preclinical Studies 256
2.3 Clinical Studies 257
2.4 Future Developments 259
3 Telomerase-Specific Gene Therapy 259
3.1 Rationale 259
3.2 Preclinical Studies 260
3.3 Clinical Studies 262
3.4 Future Developments 262
4 Oligonucleotide Targeting of Telomerase 263
4.1 Rationale 263
4.2 Preclinical Studies 263
4.3 Clinical Studies 266
4.4 Future Developments 267
5 Small Molecule Inhibitors 267
5.1 Rationale 267
5.2 Preclinical Studies 268
5.3 Clinical Studies 270
5.4 Future Developments 271
6 Applying Cell-Based Screening to Telomerase 272
7 Conclusions 275
References 276
Werner Syndrome, Telomeres, and Stress Signaling: Implications for Future Therapies? 290
1 Introduction 290
2 The WRN Gene Encodes a Structure-Specific DNA Helicase 292
3 Cellular Aspects of Werner Syndrome 295
4 The Role of Telomeres in Werner Syndrome 297
5 Genome Instability as a Hallmark of Werner Syndrome 299
6 Premature Senescence in WS Cells May be a Stress Response 300
7 Therapeutic Possibilities for Werner Syndrome 301
8 Concluding Comments 304
References 305
Index 314
Color Plates 317