Telomeres are specialized DNA-protein structures that protect the ends of chromosomes to maintain their integrity. They are chromosome sentinels. This book, written by multiple authors, presents current knowledge and the most recent discoveries relating to telomeres.
The first chapters describe telomere structures (DNA and proteins), organization, dynamics and replication in a range of organisms including ciliates, yeast and mammals. The following chapters cover mechanisms that maintain telomere length involving telomerase and Alternative Lengthening Telomeres (ALT) mechanisms. Interestingly, telomeres are transcribed into repetitive RNA called TERRA (Telomeric repeat-containing RNA), the state of the art regarding mammalian telomere transcripts is presented here.
Two chapters are dedicated to the description of how telomere biology impacts the development of cancer and how their disfunctions induce telomeropathies (telomere biology disorders). Finally, the book ends with a chapter presenting telomere and telomerase targeting agents as potential anticancer agents, a promising therapeutic approach.
Table of Contents
Foreword xiii
Julia COOPER
Chapter 1 Telomeres: All's Well That Ends Well 1
Patrizia ALBERTI
1.1 Introduction 1
1.2 The beginning of the end 2
1.3 Telomeric architectures: from ciliates to other eukaryotes 10
1.4 G-quadruplexes at telomeres 18
1.5 References 26
Chapter 2 Methods to Measure Telomere Lengths 39
Lauréline ROGER
2.1 Why does telomere length matter? 39
2.2 Methods for measuring telomere length 41
2.3 References 53
Chapter 3 The Shelterin Complex 57
Claire GHILAIN, Eric GILSON and Marie-Josèphe GIRAUD-PANIS
3.1 TRF1 and TRF2, structurally alike but… 59
3.2 RAP1 75
3.3 TIN2 79
3.4 TPP1-POT1 82
3.5 Quaternary structure of the shelterin 86
3.6 Concluding remarks 86
3.7 References 87
Chapter 4 Mammalian Telomere Organization and Dynamics in the Nuclear Volume 105
Sonia STINUS and Laure CRABBE
4.1 Introduction 105
4.2 Nuclear envelope and lamins: orchestrators of cell and genome architecture 106
4.3 Interplay between telomeres and nuclear structures 108
4.4 Telomere tethering to the NE to promote meiotic pairing 109
4.5 Telomere organization and dynamics in the nucleus 110
4.6 Interaction between telomere chromatin and lamins during post-mitotic nuclear assembly 111
4.7 Interaction between telomere chromatin and lamins for telomere maintenance 112
4.8 Conclusion 113
4.9 References 114
Chapter 5 Saccharomyces cerevisiae, a Model at the Forefront of Telomere Biology 119
Aurélia BARASCU and Maria Teresa TEIXEIRA
5.1 Introduction 119
5.2 Telomere characterization: various experimental organisms for first historical experiments 121
5.3 Protection and proliferation: the telomere dilemma 122
5.4 Telomere maintenance 129
5.5 Telomeres: one size for one identity 134
5.6 Telomeres, replicative senescence, aging and genomic instability 136
5.7 Senescence escape phenomena and genomic instability 140
5.8 Conclusion 142
5.9 References 142
Chapter 6 Dealing with Replication Stress at Telomeres 157
Stéphane COULON
6.1 Introduction 157
6.2 Removal of the DNA structures that impede RF progression 162
6.3 Accessory factors that contribute to telomere replication l 171
6.4 Concluding remarks 176
6.5 References 177
Chapter 7 A Brief History of Telomerase: Exceptional Women in Command 193
Vincent GÉLI
7.1 Acknowledgments 199
7.2 References 199
Chapter 8 Telomerase: Structure and Mechanism 205
Carole SAINTOMÉ
8.1 Introduction 205
8.2 Roles 206
8.3 Structures 207
8.4 Biogenesis 212
8.5 Mechanism 214
8.6 Regulation 215
8.7 Disease and therapy 216
8.8 Conclusion 216
8.9 References 217
Chapter 9 Alternative Lengthening of Telomeres 223
Mathilde GAUCHIER
9.1 ALT cell markers 224
9.2 ALT mechanisms 228
9.3 Replicative stress and DNA repair pathway at ALT telomeres 229
9.4 The structure of chromatin at ALT telomeres 230
9.5 ALT and cancer 232
9.6 The ALT pathway: a non-pathological function? 232
9.7 Alternative pathways not involving recombination: evolutionary aspects 233
9.8 Appendix: experimental methods that allow the identification of the ALT phenotype in human cancer cells 236
9.9 References 237
Chapter 10 TERRA, Telomeric Non-coding RNAs 245
Anabelle DECOTTIGNIES
10.1 Introduction 245
10.2 The human TERRAs 246
10.3 The mouse TERRAs 255
10.4 Conclusion 258
10.5 References 258
Chapter 11 Telomeres and Cancer 263
Arturo LONDOÑO-VALLEJO
11.1 Introduction 263
11.2 Short telomeres and telomere-induced senescence are barriers to oncogenic development 264
11.3 Excessive shortening of telomeres promotes CIN in the early stages of cancer transformation 267
11.4 The contribution of telomere-driven CIN to tumor progression 270
11.5 The senescent microenvironment promotes cancer development 271
11.6 Mechanisms of cell immortalization 273
11.7 Therapeutic potential of telomeres and telomerase and prognostic value of telomere-related evaluations 277
11.8 Conclusion 279
11.9 Acknowledgments 279
11.10 References 280
Chapter 12 Physiopathology of Telomeres 291
Caroline KANNENGIESSER and Patrick REVY
12.1 Introduction 291
12.2 Telomere length in blood 292
12.3 Different genes associated with telomere defects 295
12.4 Different diseases associated with telomere defects 300
12.5 Genetic analysis and counseling 308
12.6 Treatment of diseases associated with telomere defects 310
12.7 Compensatory somatic mutations in the TERT promoter 311
12.8 Missing heredity 312
12.9 Conclusion 313
12.10 References 313
Chapter 13 Telomeres Targeting Agents 329
Sophie BOMBARD, Patrick MAILLIET and Marie-Paule TEULADE-FICHOU
13.1 Introduction 329
13.2 Chemistry and in vitro properties of G4 ligands targeting telomeres 330
13.3 Biological properties of G4 ligands targeting telomeres 341
13.4 Metal complexes targeting telomeres 344
13.5 Compounds targeting the proteins of the human shelterin complex 348
13.6 Compounds targeting telomerase 355
13.7 General conclusion 357
13.8 Acknowledgments 358
13.9 References 358
List of Authors 373
Index 377
