Chromosomal Instability and Aging: Basic Science and Clinical Implications

Cover......Page 1
Chromosomal Instability and Aging......Page 2
ISBN-13: 9780824708566......Page 3
Foreword......Page 5
Preface......Page 8
Contents......Page 10
Contributors......Page 13
I. INTRODUCTION......Page 17
II. DEFINITIONS......Page 18
IV. WHAT IS AGING?......Page 19
V. WHY DO WE AGE?......Page 20
VI. HOW DO WE AGE?......Page 21
REFERENCES......Page 22
I. INTRODUCTION......Page 24
II. DNA DAMAGE AND REPAIR......Page 25
C. Mismatch Repair......Page 26
III. GENOME MAINTENANCE WITH AGING......Page 27
V. TELOMERES......Page 28
VI. EPIGENETIC MECHANISMS......Page 29
A. Mitochondrial Genetics......Page 30
B. Mitochondria, Aging, and Human Disease......Page 31
IX. MODEL SYSTEMS......Page 33
REFERENCES......Page 38
I. INTRODUCTION......Page 43
II. CAUSES OF CELLULAR SENESCENCE......Page 44
A. Telomeric Dysfunction......Page 45
B. DNA Damage......Page 46
C. Chromatin Perturbations......Page 47
III. SENESCENT PHENOTYPE......Page 48
B. Resistance to Apoptosis......Page 49
IV. CONTROL OF CELLULAR SENESCENCE......Page 50
V. CELLULAR SENESCENCE AND CANCER......Page 51
VI. CELLULAR SENESCENCE AND AGING......Page 52
REFERENCES......Page 54
I. INTRODUCTION......Page 64
III. TELOMERE SHORTENING......Page 65
IV. TELOMERES AND DIRECT PROOF OF THEIR REGULATION OF M1/M2......Page 67
V. “TELOMERE-INDEPENDENT” MECHANISMS OF GROWTH ARREST......Page 68
VI. MOUSE CULTURE-INDUCED GROWTH ARREST......Page 69
VIII. IMR90 AND OXYGEN: WHAT IS THE ROLE OF P16?......Page 71
IX. MECHANISMS FOR THE INDUCTION OF M1......Page 73
X. WHAT IS THE NATURE OF TELOMERIC EROSION BETWEEN M1 AND M2?......Page 76
REFERENCES......Page 80
I. INTRODUCTION: TELOMERIC DNA......Page 86
II. TELOMERIC CHROMATIN......Page 88
III. CELLULAR LOCALIZATION OF TELOMERES......Page 92
IV. TELOMERE-ASSOCIATED PROTEINS: TELOMERIC DNA–BINDING FACTORS......Page 93
B. Tankyrase......Page 96
D. Mre11 Complex......Page 98
E. Ku70/80......Page 99
VI. TELOMERIC TRACT LENGTH REGULATION IN HIGHER EUKARYOTES......Page 100
VII. TELOMERE END PROTECTION AND HIGHER ORDER ARCHITECTURE......Page 103
VIII. REPLICATION INITIATION FROM A CLEAVED T-LOOP JUNCTION: PLACING AN ORIGIN AT THE END......Page 106
IX. T-LOOP–DEPENDENT PATHWAY OF TELOMERIC ELONGATION......Page 107
X. COMPACTION OF THE T-LOOP INTO A REGULAR PARTICLE AS A MEANS OF MEASURING TELOMERE LENGTH......Page 108
REFERENCES......Page 109
I. INTRODUCTION......Page 120
II. KU BINDS DNA ENDS IN A SEQUENCE-INDEPENDENT MANNER......Page 121
III. KU BINDS TO DNA AND RNA IN A SEQUENCE-SPECIFIC MANNER......Page 122
IV. KU FORMS PROTEIN–PROTEIN INTERACTIONS......Page 123
V. TELOMERES AND TELOMERASE......Page 124
VI. KU AT THE YEAST TELOMERE......Page 125
VII. KU AT THE MAMMALIAN TELOMERE......Page 127
VIII. TELOMERIC SHORTENING AND CELLULAR SENESCENCE......Page 129
X. CONCLUSION......Page 130
REFERENCES......Page 131
I. INTRODUCTION......Page 138
A. Numerical Chromosomal Aberrations Involving the Sex Chromosomes......Page 139
C. Mechanisms of Loss of Specific Chromosomes with Aging......Page 141
D. Effects of Experimental Conditions on Numerical Chromosomal Aberrations......Page 147
A. Translocations, Chromosomal Breaks, and Fragile Sites......Page 148
IV. INFLUENCE OF DIET ON CHROMOSOMAL INSTABILITY......Page 150
V. EFFECT OF GENOTYPE ON CHROMOSOMAL INSTABILITY......Page 151
VI. CONCLUSION......Page 152
REFERENCES......Page 154
I. INTRODUCTION......Page 161
II. CHROMATIN VERSUS OTHER DETERMINANTS OF AGING......Page 162
III. EPIGENETIC MEMORY: DISTINCT REQUIREMENTS FOR INITIATION AND MAINTENANCE OF HERITABLE CHROMATINIC DOMAINS......Page 165
IV. AGE-RELATED SILENCING DEFECTS IN MAMMALS......Page 167
V. HERITABLE ACTIVE STATES AND AGE-RELATED DE NOVO SILENCING......Page 168
VI. MOLECULAR MECHANISMS INVOLVED IN CHROMATIN-DEPENDENT INHERITANCE......Page 169
VII. CHROMATINIC STRUCTURES: MANIPULATION IN MODEL SYSTEMS......Page 171
VIII. POTENTIAL CONSEQUENCES OF CHROMATIN INSTABILITY......Page 172
IX. MITOTIC VERSUS POSTMITOTIC COMPARTMENTS......Page 173
X. REMAINING ISSUES AND CONCLUSION......Page 174
REFERENCES......Page 175
I. INTRODUCTION......Page 179
II. CLINICAL FEATURES......Page 180
A. Functional Domains of WRN Gene Product......Page 181
B. WRN Mutations......Page 182
C. WRN Helicase Activity—Effect of Single-Stranded Binding Proteins and Substrate Specificity......Page 183
D. Characteristics and Significance of WRN Exonuclease Activity......Page 184
IV. WRN PROTEIN COMPLEXES AND CELLULAR FUNCTION OF WRN......Page 185
B. DNA Polymerase......Page 186
C. Homologous Recombination......Page 187
E. Telomeric Maintenance......Page 188
V. MOUSE MODELS OF WERNER SYNDROME......Page 189
VII. CONCLUSION......Page 191
REFERENCES......Page 192
I. INTRODUCTION......Page 198
II. GENOMIC INSTABILITY......Page 200
III. GENETICS OF BLOOM SYNDROME......Page 201
B. Linkage Disequilibrium......Page 202
C. High-SCE/Low-SCE Mosaicism......Page 203
D. Mutational Analysis of BLM......Page 205
IV. PRIMARY STRUCTURE OF BLM......Page 206
V. ENZYMATIC ACTIVITY OF BLM......Page 208
VI. CELL BIOLOGY OF BLM......Page 210
VII. BLM COMPLEX......Page 214
VIII. POSSIBLE MOLECULAR MECHANISMS OF BLM FUNCTION......Page 218
REFERENCES......Page 224
I. INTRODUCTION......Page 234
A. Cutaneous Signs......Page 235
C. Short Stature......Page 236
A. Cloning of RECQL4, a Member of the RecQ Helicase Gene Family......Page 237
A. Chromosomal Instability of RTS Cells......Page 241
B. Sensitivity to Ultraviolet Light and DNA-Damaging Agents......Page 242
C. Dynamics of the RECQL4 Helicase in Cells......Page 243
D. Immunological Diagnosis of RTS, WS, and BS......Page 244
A. Structural Similarities to Other RecQ Helicase Family Members......Page 245
B. Promoter and Tissue-Specific Expression of RECQL4......Page 246
C. Biochemical Properties of RECQL4 Helicase......Page 247
D. Subcellular Localization of RECQL4 Helicase......Page 248
E. RECQL4 Gene Targeting in Mice......Page 249
ACKNOWLEDGMENTS......Page 250
REFERENCES......Page 251
I. INTRODUCTION......Page 256
II. CLINICAL FEATURES......Page 257
IV. BASIC RESEARCH......Page 261
V. HYALURONIC ACID URINARY LEVELS IN PROGERIA......Page 264
VI. CHROMOSOMAL ANALYSIS IN PROGERIA......Page 266
REFERENCES......Page 269
I. INTRODUCTION......Page 274
A. Degenerative Neurologic Disease......Page 275
C. Malignancy......Page 276
G. Genetic Instability......Page 277
J. Absence of Cell Cycle Checkpoints......Page 278
L. Apoptosis, AT, and ATM Function......Page 279
M. Cellular Senescence and Telomere Abnormalities......Page 280
III. ATM GENE......Page 281
V. PHENOTYPE OF ATM KNOCKOUT MICE......Page 283
VI. DSN MODEL AS A WORKING HYPOTHESIS FOR ATM FUNCTION......Page 285
VII. DIAGNOSIS AND TREATMENT......Page 288
VIII. ETIOLOGY OF NEURODEGENERATION IN AT......Page 289
X. EVIDENCE FROM STUDIES OF AT FAMILIES......Page 290
XI. DO GERMLINE ATM MUTATIONS PLAY A ROLE IN FAMILIAL AND SPORADIC BREAST CANCERS?......Page 291
XII. DO SOMATIC MUTATIONS IN THE ATM GENE PLAY A ROLE IN SPORADIC TUMOR DEVELOPMENT?......Page 292
XIII. ATM STRUCTURE AND FUNCTION IN SPORADIC BREAST TUMORS......Page 293
XIV. FREQUENT INACTIVATION OF ATM IN SPORADIC LEUKEMIAS......Page 294
XV. ETIOLOGY OF GERMLINE CARRIERS’ CANCER RISK......Page 295
XVI. ARE THERE TWO CLINICALLY SIGNIFICANT CLASSES OF ATM MUTATION?......Page 296
B. Mammography......Page 297
XVIII. CONCLUSIONS......Page 298
REFERENCES......Page 299
I. INTRODUCTION......Page 322
II. NBS PHENOTYPES......Page 323
3. Immunodeficiency......Page 324
5. Malignancy......Page 325
1. Radiosensitivity......Page 326
2. Cell Cycle Checkpoint Deficiencies......Page 327
4. DNA Repair Defect......Page 328
A. Cloning and Structure of NBS1......Page 329
B. NBS1 Mutations......Page 331
C. Animal Models......Page 332
E. Nibrin Phosphorylation by ATM......Page 333
F. Expression of Nbn1 in Murine Development......Page 334
G. Homology Lessons from Yeast, Chicken, and......Page 335
B. In vitro Enzymatic Activities of the hMre11/hRad50/Nibrin (M/R/N) Complex......Page 337
1. hMre11-Binding Domain......Page 338
D. Association of Nibrin with BRCA1......Page 339
E. Nibrin and V(D)J Recombination......Page 340
F. Nibrin and Telomeres......Page 341
V. MODELS FOR NIBRIN FUNCTION......Page 343
REFERENCES......Page 344
I. INTRODUCTION......Page 355
A. Description of the Phenotype......Page 356
B. Variants of DKC......Page 358
A. Cell Viability......Page 359
IV. CHARACTERISTICS OF THE DKC1 GENE......Page 360
A. cDNA and Northern Blot Expression Data......Page 361
B. In Situ Expression of Dkc1 in Embryological Development: How Does This Relate to the Clinical Course of the Disease?......Page 363
C. DKC1 Gene Structure......Page 364
V. MUTATION SPECTRA AND LACK OF PHENOTYPE–GENOTYPE CORRELATIONS......Page 366
A. Properties of Dyskerin......Page 367
B. Dyskerin Localizes to the Nucleoli and Coiled Bodies......Page 370
C. Dyskerin and Its Role in rRNA and Ribosomal Biogenesis......Page 373
D. Dyskerin and Its Role in Telomeric Maintenance......Page 374
A. Yeast......Page 376
B. Drosophila......Page 377
VIII. CONCLUSION......Page 378
REFERENCES......Page 379
I. INTRODUCTION......Page 385
II. COMPLEMENTATION GROUPS......Page 386
III. GENES......Page 387
A. Gene Functions......Page 388
IV. GENETIC INSTABILITY AND DNA REPAIR......Page 390
A. Genetic Instability and Susceptibility to Clastogens......Page 392
B. Genetic Instability and Chromatin Structure......Page 393
C. Genetic Instability and Mosaicism......Page 395
D. Genetic Instability and the Cell Cycle......Page 399
E. Genetic Instability and Oxidative Stress......Page 401
V. PUZZLES AND PERSPECTIVES......Page 404
NOTE ADDED IN PROOF, JULY 2002......Page 406
REFERENCES......Page 408
I. INTRODUCTION......Page 419
II. CLINICAL PICTURE......Page 421
III. CELLULAR FEATURES AND DIAGNOSIS......Page 423
A. XPC......Page 425
B. XPE......Page 427
C. XPA......Page 428
D. XPB......Page 429
E. XPD......Page 430
F. XPG......Page 433
G. XPF......Page 434
H. XP Variants......Page 435
V. RELATIONSHIP OF MOLECULAR AND CELLULAR DEFECTS TO CLINICAL FEATURES......Page 437
REFERENCES......Page 438
II. REVIEW OF MEDICAL PROBLEMS IN ADULTS WITH DS......Page 451
a. Epilepsy......Page 452
b. Alzheimer’s Disease......Page 453
2. Eye Disorders......Page 454
4. Cardiovascular Diseases......Page 455
6. Gastrointestinal Disorders......Page 456
8. Musculoskeletal Disorders......Page 457
10. Infections......Page 458
III. IS DS A SYNDROME OF PREMATURE AGING?......Page 459
IV. HIGHLIGHTS OF EMERGING GENE INFORMATION ON CHROMOSOME 21......Page 463
V. BIOLOGY OF ALZHEIMER-TYPE DEMENTIA (AD) IN DS......Page 464
VI. ADDITIONAL GENETIC PLAYERS IN THE AD STORY......Page 465
VII. OXIDATIVE STRESS HYPOTHESIS AND AGING IN DS......Page 467
VIII. CONCLUSION......Page 468
REFERENCES......Page 469
I. INTRODUCTION......Page 475
III. CHANGES IN AGING YEAST......Page 476
IV. DNA DAMAGE AND TELOMERIC LOSS IN YEAST AGING......Page 477
VI. SILENCING AND YEAST AGING......Page 478
VII. THE “AGING LOCUS”......Page 480
A. Werner Syndrome, Rothmund–Thomson, Bloom Syndrome, and SGS1......Page 481
VIII. FURTHER TESTS OF THE ROLE OF ERCS IN YEAST AGING......Page 483
IX. CALORIC RESTRICTION AND ERC FORMATION......Page 485
X. SILENCING, RDNA CIRCLES, AND YEAST AGING......Page 486
XI. IS SGS1 AN AGING GENE?......Page 487
XII. “QUANTITATIVE” ERC DETERMINATION......Page 488
XIII. COMPUTER MODEL OF RDNA CIRCLE ACCUMULATION......Page 490
XIV. FUTURE DIRECTIONS......Page 494
XV. CONCLUSION......Page 495
REFERENCES......Page 496
I. CAENORHABDITIS ELEGANS AS A MODEL SYSTEM FOR AGING RESEARCH......Page 503
II. LONG LIFE IS ASSOCIATED WITH INCREASED RESISTANCE TO STRESS......Page 504
III. SHORT LIFE IS ASSOCIATED WITH INCREASED SENSITIVITY TO STRESS......Page 506
IV. MAINTENANCE OF THE GERM LINE......Page 507
V. POLYGENIC CONTRIBUTIONS TO AGING......Page 509
VI. HORMESIS......Page 511
VII. FUTURE PROSPECTS......Page 512
REFERENCES......Page 513
II. DROSOPHILA AS A MODEL FOR AGING STUDIES......Page 519
IV. DIFFERENTIAL GENE EXPRESSION DURING AGING......Page 521
V. TRANSGENICS......Page 522
VII. DNA REPAIR AND GENOMIC STABILITY IN DROSOPHILA......Page 523
VIII. DROSOPHILA AGING AND GENOMIC STABILITY......Page 525
REFERENCES......Page 526
A. Structure and Function of Telomeres and Telomerase......Page 533
B. Telomeres, Telomerase, and Cancer......Page 534
A. Telomeric Shortening in the Absence of Telomerase......Page 535
C. Cell Growth and Neoplastic Transformation of Cells Derived from the Telomerase Knockout Mouse: Fibroblasts versus Embryonic Stem Cells......Page 537
D. Telomerase-Independent Telomeric Rescue in Telomerase-Deficient Mice......Page 538
A. Embryonic Development......Page 540
C. Decreased Viability with Increasing Generations of Mice Deficient for Telomerase Activity......Page 541
D. The Digestive System......Page 542
E. Skin and Hair......Page 543
G. Immune System......Page 544
H. Hematopoietic System......Page 545
B. Cancer in Mice Deficient for Telomerase and the INK4a/ARF Tumor Suppressor Locus......Page 546
D. Cancer in Mice Deficient for Telomerase and the p53 Tumor Suppressor......Page 547
F. Cancer in Tissue-Specific Telomerase Transgenics......Page 548
A. Telomerase-Deficient Mice with Short Telomeres Are Hypersensitive to Ionizing Radiation......Page 549
ACKNOWLEDGMENTS......Page 550
REFERENCES......Page 551
I. INTRODUCTION......Page 557
II. OXIDATIVE STRESS AND AGING......Page 560
IV. GENETIC MODELS OF OXIDATIVE STRESS AND AGING......Page 561
V. SYNTHETIC ANTIOXIDANTS AND OXIDATIVE STRESS......Page 566
VI. FUTURE DIRECTIONS......Page 567
REFERENCES......Page 568
I. INTRODUCTION......Page 574
II. IS THERE A FINAL COMMON IF NOT UNIVERSAL PATH(S) RESULTING IN AGING?......Page 575
III. CALORIC RESTRICTION AND AGING......Page 578
IV. FUTURE DIRECTIONS......Page 579
REFERENCES......Page 580