Telomerases, telomeres, and cancer /

Section I Telomerases, Telomeres and Cancer p. 1
Section Ia Telomerase Activity and Cancer p. 2
1. The Significance of Quantitative Evaluation of Telomerase Activity and hTERT mRNA Expression in Colorectal Cancers Melissa Poggesi and Stefania Gelmini and Claudia Casini Raggi and Fabio Cianchi and Rosa Valanzano and Mario Pazzagli and Claudio Orlando p. 3
Introduction p. 3
Telomerase and Colorectal Cancer p. 3
Quantification of Telomerase Activity in Cancer p. 4
Telomerase Activity and hTERT Expression in Colon Cancer p. 4
Conclusions p. 5
Experimental Procedures p. 9
2. The Role of Telomerase De-Regulation in Keratinocyte Immortality and the Progression of Human Head and Neck Cancer E. Kenneth Parkinson p. 13
Introduction p. 13
The Immortalisation of Neoplastic Human Keratinocytes p. 15
Genetic Evidence for the Inactivation of M1 Senescence in OPLs and SCC-HN: the Role of p16[superscript INK4A] and p53 p. 17
The Role of M2 Crisis in the Suppression of Human Squamous Neoplasia p. 17
The Genetics of SCC-HN Progression In Vivo: Do They Reflect the Acquisition of Immortality In Vitro? p. 19
Conclusions and Further Questions p. 20
3. Telomerase in Mesothelioma: Diagnostic and Therapeutic Applications Karl Dhaene p. 24
Introduction p. 24
Telomerase Activity in Malignant Mesothelioma p. 25
Gene Expression Profile of Components of Telomerase in Mesothelioma p. 30
Detection of Telomerase at the Cellular Level p. 31
hTERC Anti-Sense Inhibition of Telomerase-Function in Mesothelioma Cell Lines p. 34
Conclusions p. 35
Future Perspectives p. 37
4. Telomerase Activity in Mesenchymal Tumors Regine Schneider-Stock and Carsten Boltze and Albert Roessner p. 41
Introduction p. 41
Results of Telomerase Activity Analyses in Selected Tumor Entities p. 41
Telomerase Activity and the Phenomenon of Telomeric Association p. 44
Summary p. 45
5. Telomerase Activity in Neuroblastomas: A New Molecular Marker for Treatment Stratification and Prognostic Grouping Christopher Poremba and Barbara Dockhorn-Dworniczak p. 47
Introduction: Clinical Aspects and Molecular Biology of Neuroblastoma p. 47
Telomerase and Telomeres p. 47
What is the Role of Telomerase in Neuroblastomas? p. 48
Conclusions: Telomerase Activity as New Molecular Marker for Treatment Stratification and Prognostic Grouping p. 53
6. Telomerase and Radiosensitivity of Human Tumors Tej K. Pandita p. 60
Introduction p. 60
Telomerase in Cell Proliferation and Development p. 61
Telomerase Activity and Ionizing Radiosensitivity p. 70
Telomere Dysfunction and Ionizing Radiation Sensitivity p. 73
7. Amplification of hTERT, the Telomerase Reverse Transcriptase Gene in Human Cancers Dawei Xu and Anju Zhang and Mi Hou and Magnus Bjorkholm and Astrid Gruber p. 79
Introduction p. 79
FISH Analysis Reveals hTERT Gene Amplification in Cell Lines and Tumors p. 80
Conclusions p. 81
8. Telomerase Activity as a Marker of Tumor Cell Survival to Evaluate Sensitivity of Neoplastic Cells to Cancer Treatment Isabella Faraoni and Enzo Bonmassar p. 84
Introduction p. 84
The In Vitro Chemosensitivity Assays and the Possible Role of R-TRAP p. 85
Experimental Approaches p. 87
The In Vitro R-TRAP Assay for Antitumor Cell-Mediated or Antibody-Mediated Cytotoxicity p. 95
Acknowledgments p. 96
Section Ib Telomerase-based Approaches for Cancer Therapies p. 99
9. PNA and Oligonucleotide Inhibitors of Human Telomerase Gerald Gavory and Shankar Balasubramanian p. 100
Abbreviations p. 100
Introduction p. 100
The "Antisense" Approach to Telomerase Inhibition p. 101
Oligonucleotide Analogues as Human Telomerase Inhibitors p. 103
Cell Based Studies and In Vivo Therapy p. 107
Conclusion and Future Perspectives p. 110
10. Potential of the Telomerase Catalytic Subunit as a Universal Tumor-Associated Antigen for Cancer Immunotherapy Robert H. Vonderheide and William C. Hahn p. 114
Introduction p. 114
Clinical Progress in Tumor Immunity p. 114
Search for Universal Tumor Antigens p. 116
Identification of hTERT as a Widely Expressed Tumor-Associated Antigen p. 116
Prospect of hTERT as a Clinical Target for Immunotherapy p. 118
Conclusions p. 119
Section II Structure and Function of Telomerases and Telomeres p. 121
Section IIa Humans p. 122
11. The Makings of Telomerases Joachim Lingner and Christian Wenz p. 123
Introduction p. 123
The End Replication Problem p. 123
Telomerase RNA p. 125
Telomerase Reverse Transcriptase p. 127
Telomerase-RNA Associated Proteins Involved in Maturation and Stability: La, Sm, Dyskerin p. 128
Chaperone Proteins Promote Telomerase Assembly p. 129
The Telomerase-Telomere Interaction is Mediated by Est1p p. 129
Multimerization of Telomerase p. 129
Conclusion p. 130
12. Regulation of Telomerase Activity Jun-Ping Liu and Siddhartha Deb and He Li p. 134
Introduction p. 134
Telomerase Catalytic Subunit (TERT) Gene Expression p. 135
Alternative Splicing of hTERT RNA Transcript p. 143
Post Translational Modification: Protein Phosphorylation and Dephosphorylation p. 144
Intra- and Inter-Molecular Interactions p. 147
Concluding Remarks p. 152
13. Telomeres and Mechanisms of DNA Double Strand Break Repair Predrag Slijepcevic p. 160
Introduction p. 160
Mechanisms of DSB Repair p. 160
Telomeres and DSB Repair p. 161
Telomere Maintenance in Mammalian Cells Deficient in NonDSB Repair Pathways p. 164
Interaction of Telomeric and DSB Repair Proteins p. 164
Implications p. 165
14. Roles for hTERT and Telomerase in Cell Differentiation and Apoptosis Mark P. Mattson and Peisu Zhang and Weiming Fu p. 168
Introduction p. 168
Roles for Telomerase in Cell Proliferation and Differentiation p. 168
Mechanisms of Regulation of Neuronal Differentiation by Telomerase p. 170
Apoptosis in Development, Adult Plasticity and Disease p. 171
Anti-Apoptotic Actions of Telomerase Activity and TERT p. 172
Molecular Mechanisms Underlying the Anti-Apoptotic Actions of Telomerase p. 174
Possible Clinical Applications of Telomerase Modulation p. 176
Section IIb Ciliates, Yeasts and other Eukaryotes p. 181
15. Human, Mouse and Yeast Telomerase Tara J. Moriarty and Chantal Autexier p. 182
Introduction p. 182
Telomerase Components p. 182
Telomerase Reverse Transcriptase p. 183
Telomerase RNA p. 188
Telomerase-Associated Proteins p. 192
Mechanism of Telomere Synthesis by Telomerase p. 194
Conclusions p. 198
16. The Biology of Telomeres in Hypotrichous Ciliates Franziska Jonsson and Hans J. Lipps p. 205
Introduction p. 205
The Genome of Hypotrichous Ciliates p. 207
Macronuclear Differentiation in Hypotrichs p. 209
The Telomeres of Hypotrichous Ciliates p. 212
The Telomerase of Hypotrichs p. 217
In vivo Telomere Interactions and Contribution to Macronuclear Structure p. 217
17. DNA Primer Extension by Telomerase Haim Manor and Yonit Haviv and Nava Baran p. 223
Introduction p. 223
Structure and Assembly of the Telomerase Ribonucleoprotein p. 223
Detailed Analysis of Primer Extension by the Telomerase p. 227
Updated Model for Primer Extension by Telomerase p. 234
18. Yeast Telomerases: Structure, Mechanisms and Regulation Neal F. Lue p. 239
Introduction p. 239
Telomerase Components p. 239
Biochemistry of Yeast Telomerase p. 247
Regulation of Yeast Telomerase p. 252
Conclusions p. 254
19. RAP1 Binding and Length Regulation of Yeast Telomeres Johan Wahlin and Marita Cohn p. 259
Domain Structure p. 259
DNA Binding p. 261
RAP1 Homologues p. 266
Abundance and Nuclear Localization p. 268
Function p. 271
Concluding Remarks p. 277
20. Linear Plasmids in Yeasts and Filamentous Fungi Livia Civitelli and Fiorentina Ascenzioni p. 282
Introduction p. 282
Natural Linear Plasmids in Yeasts p. 283
Natural Linear Plasmids in Filamentous Fungi p. 284
Artificial Linear Plasmids in Yeast p. 285
Replication Mechanisms p. 286
21. New Telomere Formation During the Process of Chromatin Diminution in the Parasitic Nematodes Ascaris suum and Parascaris univalens Fritz Muller p. 291
Introduction p. 291
Chromatin Diminution Consists of Chromosomal Fragmentation and Elimination of Genetic Material from All Presomatic Cells p. 292
Breakdown of the Chromosomes During Chromatin Diminution is Preceded by Extensive Structural Changes of the Chromatin p. 292
Chromatin Diminution Involves Chromosomal Breakage and New Telomere Formation Occurring Within Specific Chromosomal Regions (CBRs) p. 293
Somatic Telomeres May be Formed by a Specialized Telomerase Activity p. 295
The A. Suum Telomerase Activity is Developmentally Regulated p. 296
Chromosome Breakage and New Telomere Addition May Occur During the S-phase Preceding the Diminution Mitoses p. 296
Chromatin Diminution May Act as a "Gene Throw Away" Approach to Gene Silencing p. 297
22. Telomerase Activity in Sponges (Porifera), the Closest Related Taxa of the Hypothetical Ancestral Animal the Urmetazoa Werner E.G. Muller p. 300
Introduction: Urmetazoa - Hypothetical Ancestor of Metazoa p. 300
Primmorphs: Model System to Study the Differentiation State of Sponge Cells p. 302
Telomerase Activity in Tissue from S. domuncula and G. cydonium p. 302
Telomerase Activity in Dissociated Sponge Cells p. 303
Telomerase Activity in Primmorphs of S. domuncula p. 304
Control of Cell Homeostasis in Sponges: Apoptosis p. 305
Telomerase Activity in S. domuncula in Response to Apoptotic Stimuli p. 308
Conclusions p. 309
23. Structure and Maintenance of Chromosome Ends in Plants Jirf Fajkus and Ulrike Zentgraf p. 314
Introduction p. 314
DNA Sequences Constituting Plant Telomeres p. 315
Subdomain Structure of Chromosome Termini p. 316
Stable Telomere Maintenance in Plants p. 319
Nuclear Localization of Plant Telomeres p. 326
Section III Maintaining Telomeres without Telomerase p. 333
24. Telomeres without Telomerase in Saccharomyces cerevisiae Edward J. Louis p. 334
Introduction p. 334
Telomere Erosion When Telomerase Function is Lost p. 335
Two Types of 'Survivors' in the Absence of Telomerase p. 338
Survival in the Absence of Telomerase Requires Homologous Recombination p. 339
The Survival Pathways Have Other Genetic Requirements p. 340
Mechanisms of ALT p. 341
RAD52 Independent Mechanisms? p. 343
Unanswered Questions and Future Directions p. 344
25. Recombinational Telomere Elongation in the Yeast Kluyveromyces lactis Michael J. McEachern p. 347
Introduction p. 347
Telomere Structure in K. lactis p. 347
Deleting Telomerase Causes Progressive Telomere Shortening and Cell Senescence p. 348
Senescence Caused by terl Deletions is Due to Shortened Telomeres, Not Absence of Telomerase p. 349
Post-Senescence Survivors Emerge with Restored Growth Rates p. 350
Survivors Contain Telomeres that were Elongated through Recombination p. 350
Survivor Telomeres and Growth Phenotypes are Unstable p. 351
Regions Near Short Telomeres are Subject to High Rates of Recombination p. 353
Mismatch Repair Influences the Rate of Survivor Emergence p. 353
Common Telomeric Patterns Are Present in Elongated Telomeres within a Given Survivor p. 354
Models for Recombinational Telomere Elongation p. 355
Circles with Telomeric Repeats Can Very Effectively Promote Telomere Elongation p. 355
The 'Roll and Spread' Model of Recombinational Telomere Elongation p. 356
Can Circles Promote Telomere Elongation in Other Organisms? p. 356
26. Telomere Maintenance in Human Cell Lines and Tumors without Telomerase Clare L. Fasching and Roger R. Reddel p. 359
Introduction p. 359
Evidence for the Existence of ALT in Cell Lines in vitro Immortalized Cell Lines p. 359
Further Evidence that Telomerase is not Involved in the ALT Mechanism p. 360
ALT in Human Tumors and Tumor-Derived Cell Lines p. 362
ALT-Associated PML Bodies (APBs) p. 364
Evidence for the Involvement of Recombination in ALT p. 365
Coexistence of ALT and Telomerase p. 366
Repression of ALT p. 368
Perspectives p. 370
Section IV Non-Classical Telomere Structures p. 375
27. Telomeres in Drosophila and Other Insects Harald Biessmann and Marika F. Walter and James M. Mason p. 376
Introduction p. 376
Telomere Elongation: Mechanisms in Insects p. 376
Retrotransposition in Drosophila melanogaster p. 378
Chromosome Capping in Drosophila p. 384
Telomeric Silencing and TAS p. 386
Conclusions p. 390
28. Mitochondrial Telomeres: Alternative Solutions to the End-Replication Problem Jozef Nosek and Lubomir Tomaska p. 396
Introduction p. 396
Linear Mitochondrial Genomes: More Than an Evolutionary Oddity p. 396
The Concept of Mitochondrial Telomeres p. 399
Variability of Mitochondrial Telomeric Structures p. 399
Mitochondrial Telomeric Proteins p. 402
Mitochondrial Telomeric Minicircles p. 403
Evolutionary Considerations p. 407
Medical Implications p. 410
Index p. 418