Telomeres

Carole Saintomé is Assistant Professor in Biochemistry at Sorbonne Université, France. She studies the role of single-stranded DNA binding proteins at telomeres and their interactions with G-quadruplexes DNA structures at the Muséum national d'Histoire naturelle, France.

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