GENOME INSTABILITY IN CANCER DEVELOPMENT Edited by Erich A Nigg Image (kindly provided by Dr M Speicher): Metaphase spread of small cell lung cancer cell line H187 after M FISH hybridization The metaphase spread is hyper diploid and has 53 chromosomes Numerous structural aberrations, such as translocations, insertions and deletions are visible (see also Chapter 1.2) ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY Editorial Board: NATHAN BACK, State University of New York at Buffalo IRUN R COHEN, The Weizmann Institute of Science DAVID KRITCHEVSKY, Wistar Institute ABEL LAJTHA, N S Kline Institute for Psychiatric Research RODOLFO PAOLETTI, University of Milan Recent Volumes in this Series Volume 491 THE MOLECULAR IMMUNOLOGY OF COMPLEX CARBOHYDRATES-2 Edited by Albert M Wu Volume 492 NUTRITION AND CANCER PREVENTION: New Insights into the Role of Phytochemicals Edited under the auspices of the American Institute for Cancer Research Volume 493 NEUROIMMUNE CIRCUITS, DRUGS OF ABUSE, AND INFECTIOUS DISEASES Edited by Herman Friedman, Thomas W Klein, and John J Madden Volume 494 THE NIDOVIRUSES (CORONAVIRUSES AND ARTERIVIRUSES) Edited by Ehud Lavi, Susan R Weiss, and Susan T Hingley Volume 495 PROGRESS IN BASIC AND CLINICAL IMMUNOLOGY Edited by Andrzej Mackjewicz, Maciej Kurpisz, and Jan Zeromski Volume 496 NONINVASIVE ASSESSMENT OF TRABECULAR BONE ARCHITECTURE AND THE COMPETENCE OF BONE Edited by Sharmila Majumdar, Ph.D., and Brian K Bay, Ph.D Volume 497 INTRACTABLE SEIZURES: Diagnosis, Treatment, and Prevention Edited by W McIntyre Burnham, Peter L Carlen, and Paul A Hwang Volume 498 DIABETES AND CARDIOVASCULAR DISEASE: Etiology, Treatment, and Outcomes Edited by Aubie Angel, Naranjan Dhalla, Grant Pierce, and Pawan Singal Volume 499 FRONTIERS IN MODELING AND CONTROL OF BREATHING Edited by Chi-Sang Poon and Homayoun Kazemi Volume 500 BIOLOGICAL REACTIVE INTERMEDIATES VI: Chemical and Biological Mechanisms of Susceptibility to and Prevention of Environmental Diseases Edited by Patrick M Dansette, Robert Snyder, Marcel Delaforge, G Gordon Gibson, Helmut Greim, David J Jollow, Terrence J Monks, and I Glenn Sipes A Continuation Order Plan is available for this series A continuation order will bring delivery of each new volume immediately upon publication Volumes are billed only upon actual shipment For further information please contact the publisher GENOME INSTABILITY IN CANCER DEVELOPMENT Edited by Erich A Nigg Max-Planck Institute of Biochemistry, Martinsried, Germany ISBN-10 1-4020-3763-5 (HB) ISBN-13 978-1-4020-3763-4 (HB) ISBN-10 1-4020-3764-3 (e-book) ISBN-13 978-1-4020-3764-1 (e-book) © 2005 Springer Science + Business Media, Inc All rights reserved This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science + Business Media, Inc., 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden The use in this publication of trade names, trademarks, service marks and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights Printed in the Netherlands springeronline.com TABLE OF CONTENTS Preface vii List of Contributors ix Part The Problem of Genome Instability 1.1 The Multiplicity of Mutations in Human Cancers Ranga N Venkatesan and Lawrence A Loeb 1.2 Monitoring Chromosome Rearrangements Michael R Speicher 19 Part DNA Repair and Mutagenesis 2.1 Nucleotide Excision Repair and its Connection with Cancer and Ageing Jaan-Olle Andressoo, Jan H.J Hoeijmakers and Harm de Waard 2.2 DNA Mismatch Repair and Colon Cancer Giancarlo Marra and Josef Jiricny 45 85 2.3 Base Excision Repair Lisiane B Meira, Nicholas E Burgis and Leona D Samson 125 2.4 Genomic Instability in Cancer Development Penny A Jeggo 175 2.5 Translesion Synthesis and Error-Prone Polymerases Catherine M Green and Alan R Lehmann 199 Table of Contents vi Part Cell Cycle Progression and Chromosome Aberration 3.1 The INK4A/ARF Network – Cell Cycle Checkpoint or Emergency Brake? Ana Gutierrez del Arroyo and Gordon Peters 3.2 DNA Replication and Genomic Instability Wenge Zhu, Tarek Abbas and Anindya Dutta 227 249 3.3 The Dream of every Chromosome: Equal Segregation for a Healthy Life of the Host Tomohiro Matsumoto and Mitsuhiro Yanagida 281 3.4 Telomere Structural Dynamics in Genome Integrity Control and Carcinogenesis Roger A Greenberg and K Lenhard Rudolph 311 3.5 Gene Amplification Mechanisms Michelle Debatisse and Bernard Malfoy 3.6 DNA Methylation Instabilit y Melanie Ehrlich and Cancer-Associated 343 Genetic 3.7 Deregulation of the Centrosome Cycle and the Origin of Chromosomal Instability in Cancer Wilma L Lingle, Kara Lukaswiewicz and Jeffrey L Salisbury 363 393 Part Genome Integrity Checkpoints 4.1 Mammalian DNA Damage Response Pathway Zhenkun Lou and Junjie Chen 425 4.2 ATM and Cellular Response to DNA Damage Martin F Lavin, Sergei Kozlov, Nuri Gueven, Cheng Peng, Geoff Birrell, Phillip Chen and Shaun Scott 457 4.3 Index Mitotic Checkpoint, Aneuploidy and Cancer Tim J Yen and Gary D Kao 477 501 PREFACE Research over the past decades has firmly established the genetic basis of cancer In particular, studies on animal tumour viruses and chromosome rearrangements in human tumours have concurred to identify so-called ‘proto-oncogenes’ and ‘tumour suppressor genes’, whose deregulation promotes carcinogenesis These important findings not only explain the occurrence of certain hereditary tumours, but they also set the stage for the development of anti-cancer drugs that specifically target activated oncogenes However, in spite of tremendous progress towards the elucidation of key signalling pathways involved in carcinogenesis, most cancers continue to elude currently available therapies This stands as a reminder that “cancer” is an extraordinarily complex disease: although some cancers of the haematopoietic system show only a limited number of characteristic chromosomal aberrations, most solid tumours display a myriad of genetic changes and considerable genetic heterogeneity This is thought to reflect a trait commonly referred to as ‘genome instability’, so that no two cancers are ever likely to display the exact same genetic alterations Numerical and structural chromosome aberrations were recognised as a hallmark of human tumours for more than a century Yet, the causes and consequences of these aberrations still remain to be fully understood In particular, the question of how genome instability impacts on the development of human cancers continues to evoke intense debate Is the observed instability merely a consequence of advanced tumour growth or does it constitute a prerequisite for the acquisition of an ever more aggressive cancer cell phenotype? At what time in the evolution of a tumour does genome instability arise and what are the implications of this trait for the design of therapeutic approaches ? To answer these important questions it will be indispensable to understand the mechanisms that give rise to genome instability This information will then hopefully provide insight into the contribution of genome instability to cancer development and its relevance to therapy Preface viii Recent years have seen a surge of renewed interest in the role of genome instability in cancer Remarkable progress has been made towards understanding genome instability at the nucleotide level Specifically, several hereditary cancer susceptibility syndromes have been linked to genetic defects in DNA repair systems, notably nucleotide excision repair (NER) and mismatch repair (MMR) Moreover, genetic connections have also been established between aneuploidy (numerical chromosome imbalances) and carcinogenesis Taken together, these findings provide strong support for the hypothesis that genome instability is an important parameter in the aetiology and clinical behaviour of cancer In expanding cell populations, genome instability is expected to increase the probability of acquiring critical mutations, notably the gain of activated oncogenes and the loss of tumour suppressor genes Genome instability is also expected to favour the adaptation of incipient tumour cells to changing physiological conditions during tumour progression And, last but not least, genome instability is likely to play an important role in the emergence of resistance to therapy This book explores the molecular origins of genome instability and discusses its impact on cancer development It reviews both genetic and biochemical research on the mechanisms that allow cancer cells to accumulate critical mutations and thus evolve, through processes reminiscent of Darwinian selection, an ever increasingly aggressive behaviour By bringing together authoritative reviews from experts in widely different but complementary fields, the book is meant to stimulate thought, discussion and experimentation Hopefully, it will serve as a rich source of information for a wide audience, including advanced students, researchers and oncologists My sincere thanks go to all authors for contributing excellent and comprehensive chapters, to Dr M Speicher for kindly providing the internal cover picture, to Ms Alison Dalfovo for expert secretarial assistance, and to Dr Cristina Alves dos Santos and her colleagues at Springer Life Sciences for a very pleasant collaboration throughout the preparation of this book Martinsried, Spring 2005 Erich A Nigg LIST OF CONTRIBUTORS Tarek Abbas Department of Biochemistry and Molecular Genetics University of Virginia School of Medicine Charlottesville, VA 22908 USA Jaan-Olle Andressoo MGC Department of Cell Biology and Genetics Center for Biomedical Genetics Erasmus Medical Center 3000 DR Rotterdam The Netherlands Geoff Birrell The Queensland Institute of Medical Research 300 Herston Rd Herston Qld 4029 Australia Nicholas E Burgis Division of Biological Engineering Massachusetts 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X., A Abrieu, Y Zheng, K.F Sullivan, and D.W Cleveland 2000 CENP-E forms a link between attachment of spindle microtubules to kinetochores and the mitotic checkpoint Nat Cell Biol 2:484-91 INDEX 14-3-3 proteins, 366, 441, 469 2-acetylaminofluorene-guanine (AAF-G), 129ff, 160, 207f, 3’ phosphodiesterase, 153 5,6-dihydrouracil, 149, 151 53BP1, 179, 427f, 434, 436, 441f, 468 5-azacytidine, 365f, 372, 379, 382 5-azadeoxycytidine, 372, 374 5-hydroxycytosine, 147, 151 5-hydroxyuracil (5-OHU), 151 8-oxoguanine, 144, 208 Abasic site, 126, 144, 149, 203 ABC (ATP binding cassette), 92 Accelerated ageing, 46, 53, 55, 66, 69, 71 Acetylation, 150, 185, 251, 268, 366, 368, 375, 379 Acid catalysis, 132 Acrocentric chromosomes, 26, 380 Acute myeloid leukemia (AML), 351f, 367 Adenoma, 328 Adenomatous Polyposis Coli (APC), 101, 484 Aenomatous polyps, 106 Adenovirus, 231, 267, 463 Ageing, v, 45f, 54, 56, 60, 62, 67, 69, 71f , 75, 107 AID (activation-induced cytidine deaminase), 10 Alkylation, 27, 111, 128ff, 316 Allelic imbalance (AI), 35 Alu repeats, 23, 377f AML: see acute myeloid leukemia Amplicons, 349ff Anaphase bridges, 327, 330, 345, 348f Anaphase Promoting Complex/Cyclosome (APC/C), 259, 294, 479, 481ff, 494 Anchorage independence, 492 Aneuploidy, 3f, 20, 181f, 294, 299f, 330, 363, 368, 377, 393f, 399ff, 477f, 483ff Aneuploidy hypothesis, 20 Ankyrin-like repeats, 227 Antibody diversification, 139, 160 Antioxidants, 154 Antisense, 209, 492 APC/C: see Anaphase Promoting Complex/Cyclosome AP-endonuclease, 129, 148, 152 APOBEC-1, 10, 139 Apoptosis, 9, 14, 50, 55, 63, 65, 67, 69, 71, 75, 103f, 125, 177, 179, 181, 185, 187, 239, 254, 502 267f, 312, 325, 329f, 366, 400, 407f, 425, 431, 434, 437, 442f, 490 Apurinic/apyrimidinic (AP), 126 Arf (alternative reading frame), 228 Array based technologies, 32 Array painting, 27 Artemis, 177, 187, 189, 348 Ataxia-telangiectasia (AT), 55ff, 105, 178, 188, 269, 315f, 429, 457ff ATM kinase, 316, 430, 462ff ATM/ATR, 236ff, 316ff, 323, 431ff, 442 ATPases, 92, 94, 251f, 292, 429 ATR kinase, 105, 181f, 261, 268, 316ff, 349, 430ff, 466 ATRIP, 316, 430, 431, 432 ATR-Seckel Syndrome, 182 Aurora kinases, 289f, 398, 404, 480, 494 Autonomously replicating sequences (ARS), 250 AZT (Azidothymidine), 155 BACH1, 435 Balanced chromosome rearrangements, 31 Banding analysis, 24 BARD1, 181, 400, 435 Barrett’s esophagus, Basal cell carcinomas (BCC), 58 Base excision repair (BER), 12f, 47f, 52f, 70, 73, 75, 95, 105, 126ff, 211 Base-substitution, 85 Bax, 185, 442 Benzo[a]pyrene (BaP), 207 BER: see base excision repair BFB: see breakage-fusion-bridge cycles Biorientation, 284, 290 Bipolar spindle, 396, 401, 407ff Bleomycin, 427, 460 BLM, 110, 269, 435, 458 Index Bloom syndrome, 6, 105, 269, 458, 491 Bmi1, 235f BRCA1, 34, 179ff, 315f, 321, 349, 366, 397, 400, 408, 425, 427, 431ff, 463, 467ff BRCA1-associated genome surveillance complex (BASC), 435 BRCA2, 178ff, 269, 321, 397, 400, 408, 435, 493 BRCT domains, 181, 209, 427, 429, 434ff Breakage-fusion-bridge (BFB) cycles, 345ff Breast cancer, 29, 133, 180, 188f, 298, 328, 355, 405, 435, 461, 492 Brittle hair and nails, 57, 62 Bromodeoxyuridine, 212 Bub1, 4, 188, 291, 479ff Bub3, 479, 481, 484f, 487f BubR1, 188, 291, 298, 479, 480ff Caffeine, 207, 268 CAK (Cdk-activating kinase), 53, 71 Cancer incidence, 7, 63, 66, 160, 188f, 371 Cancer predisposition, 54, 62, 64, 66, 71, 98, 106, 159, 175, 180, 185ff, 316, 371, 393, 425, 458 Cancer risk, 46, 53, 62f, 110, 158, 160, 461f Cancer susceptibility, 46, 63, 97f, 141, 237 Carcinogenesis, 4, 6, 20, 27, 29, 49, 53, 62ff, 101, 105, 132, 218, 299, 311, 326ff, 363, 371, 374, 376f, 381f, 477, 484, 491 Caspase, 65, 366, 408 CBP/p300, 141 Cdc6, 252f, 253, 256ff, 265ff Cdc7/Dbf4, 260 Cdc20, 294, 295, 481ff Cdc25 phosphatase, 268, 467 Cdc45, 255ff, 258, 260f, 468 Index CDE I, II, and III 285, 287 Cdk: see cyclin dependent kinases Cdt1, 256ff Cell cycle, 14, 53, 65, 103, 125, 147, 150, 176ff, 199, 215, 227, 230ff, 249ff, 270, 281f, 287, 292, 294, 301, 312, 315, 318, 329, 343f, 347, 351, 366f, 395ff, 408, 410, 425, 431, 434, 437, 457, 463ff, 483, 491f - G1 phase, 177, 230, 253, 255, 256, 258f, 262, 265f, 351, 469 - G2/M, 179, 181, 262, 264, 267f, 290, 316, 398ff, 430ff, 441f, 467ff - S phase, 135, 147, 154, 157, 228, 252, 263, 315ff, 468 Cell cycle arrest, 65, 125, 177, 230f, 234, 312, 329, 397, 491 Cell cycle checkpoint, 14, 177, 179, 181, 187f, 199, 227, 315, 344, 366, 398, 408, 410, 425, 431, 434, 437, 457, 463f, 466f, 470 - G2/M checkpoint, 267f, 316, 399f, 430ff, 467ff - G1/S checkpoint, 400, 438f, 443, 466f Cell death, 46, 50, 61, 63, 99, 101, 125, 175, 186f, 266, 289, 299, 314, 320, 326, 394, 397, 408, 490, 492 Cellular senescence, 46, 63, 325 CENP-A, 286ff, 299f CENP-C, 287 CENP-E, 289f, 483 CENP-I, 287, 291, 481, 483 Central Nervous System (CNS), 55 Centrioles, 394ff, 401, 403, 407 - Centriole disjunction, 398 - Centriole duplication, 395, 397, 399ff Centromeres, 23f, 285f, 288, 290, 297, 299, 374, 478 503 Centromeric heterochromatin, 288, 377, 381 Centrosomes, 181f, 252, 281, 393ff, - Centrosome amplification, 181, 299, 394f, 399f, 404ff - Centrosome cycle, 395, 397ff, 404, 410 - Centrosome doubling, 395ff, 403 - Centrosome maturation, 401, 403 - Centrosome separation, 399, 401 Cerebro-oculo-facio-skeletal syndrome (COFS), 54 CGH: see comparitive genomic hybridization Checkpoint pathways, 200, 268f Chemical carcinogen, 4, 64, 238 Chemotherapeutic agents, 13, 128, 218 Chk1, 253, 267f, 317, 430ff, 437, 440ff Chk2, 179, 253, 267f, 298, 315, 317, 323, 427, 431ff, 441ff, 466ff Chromatin, 5, 23, 28f, 103, 144, 184, 206, 212f, 236, 251, 253, 255f, 258, 261ff, 293f, 297ff, 315f, 320, 363ff, 375, 377, 379, 393, 428ff, 436, 464f, 470 Chromosomal instability (CIN), 5f, 14, 20, 27, 30, 103, 105, 111, 404ff, 477 Chromosomal mosaic analysis, 27 Chromosome, 3ff, 9, 13f, 19ff, 99f, 104, 109, 142, 146f, 181ff, 225, 228, 252, 257, 281ff, 315, 317, 320, 330, 343ff, 364f, 369ff, 380ff, 393ff, 404ff, 457, 460, 466, 477ff, 491ff - Chromosome aberrations, 181f - Chromosome breakage, 330, 345, 350, 369f - Chromosome cohesion, 291, 301 504 - Chromosome condensation, 182, 281, 289, 296ff - Chromosome congression, 252, 289 - Chromosome dynamics, 281 - Chromosome microdissection, 24 - Chromosome missegregation, 394, 407, 410 - Chromosome movements, 283 - Chromosome painting, 23f 27 - Chromosome passenger, 289 - Chromosome rearrangements, 19ff, 36, 348f, 371ff - Chromosome segregation, 4, 9, 14, 181, 252, 288f, 293, 296, 298f, 364, 394, 407, 478, 494 - Chromosome territories, 28, 30 Cigarette smoke, 46, 146 CIN: see chromosomal instability Cisplatin, 47, 111 Clamp loader, 50, 212ff, 430 Clamp unloader, 214 Claspin, 431 Clonal selection, 7, 9, 11f, 14, 101 c-myc, 66, 189, 348, 380 Cockayne syndrome (CS), 54f Cohesion, 204, 281, 289, 291ff, 300, 398, 401 Colchicine, 469 Colorectal cancer (CRC), 6, 9, 12, 20, 85, 97, 99, 103, 107, 109, 132, 143, 159f, 299, 327, 365f, 425, 477, 484f Common fragile sites (CFSs), 346 Comparative genomic hybridization (CGH), 5, 31, 32ff Complementation group, 57f, 67f Condensin complex, 289, 297f, 301 Confocal microscopy, 28f Constitutive heterochromatin, 368, 373, 381 COP9 signalosome, 66 Index Cornelia de Lange syndrome (CdLS), 300 CPD: see cyclobutane pyrimidine dimer CRC: see colorectal cancer CS: see Cockayne syndrome Cse4, 287 Cyclin dependent kinase (Cdk), 228, 249, 253, 257,260ff, 398, 438, 401, 440f, 468f Cyclobutane pyrimidine dimer (CPD), 47ff, 54, 64, 204, 207f, 210 Cyclooxygenases, 46 Cytokinesis, 252, 289, 297, 395f, 400f, 403, 406, 410 Cytosine methylation, 363, 368 Cytotoxic drugs, 343f Damage recognition factors, 49 Damage response pathways, 148, 175 Deamination, 10, 102, 127, 131, 133, 135, 139, 141 Demyelinating neuropathy, 62 Deoxyadenine methylase (Dam), 95 Deoxycytidine nucleotidyl transferase, 204 Depurination, 126, 152 Dicentric chromatid, 287, 460 Dihydrofolate reductase (DHFR), 250, 343 DNA bubble structures, 151 DNA damage, 12, 46ff, 62ff, 73, 105, 125, 127f, 131, 133, 148f, 154, 159, 179ff, 200, 213ff, 232ff, 256, 267ff, 296, 311f, 315ff, 322ff, 329, 366, 400, 408, 425ff, 458, 462, 464ff, 493 DNA glycosylases, 126, 129ff, 135, 142, 145, 147, 152, 155 DNA helicase, 254, 318, 322, 435 DNA hypomethylation, 365, 368f, 372ff Index DNA lesions, 10, 48, 52f, 58, 63, 65, 75, 131, 154, 159f, 316, 425, 470 DNA ligase I, 50, 87, 90, 152, 154, 157ff, 177, 183, 185f, 189, 458 DNA ligase IV, 177, 183, 185f, 189, 458 DNA methylation, 363ff, 372, 376ff DNA methylation inhibitor, 365, 372 DNA methyltransferase, 365ff 372, 379, 380 DNA mismatch repair, 88, 425, 477 DNA N-glycosylase, 149ff DNA polymerase, 7, 9ff, 50, 54, 85ff, 96ff, 127f, 148, 155, 159, 199, 203ff, 255, 257f, 260f, 430 DNA repair, 9, 11f, 14, 35, 45ff, 57, 59, 61, 65ff, 73, 87, 102, 125f, 139, 152ff, 176, 181, 188, 249, 315ff, 365f, 400, 428, 431, 433, 457, 466, 470 DNA replication, 8, 13, 23, 50, 53, 85ff, 95ff, 110, 125, 158, 199, 230, 249ff, 292f, 316, 318, 323, 351, 364, 397, 398ff, 430, 433f, 468, 477, 491 DNA-damaging agents, 201 DNA-dependent protein kinase, 177f, 183ff, 189f, 320, 346ff, 427f, 431f, 437, 462 Double minute (DM) chromosomes, 30, 343 Double strand breaks (DSB), 128, 175ff, 315ff, 345ff, 427ff Drosophila melanogaster, 59, 251, 320 DSB: see double strand breaks Dynactin, 290 Dynein, 289f, 300, 399 E coli, 91ff, 129, 141ff, 147, 150ff, 201ff, 212, 214, 218 505 E2 ubiquitin-conjugating enzyme, 214 E2F, 228, 230, 232, 236, 399, 434, 437, 443, 466 E3 ubiquitin ligase, 214, 228, 231, 263, 435, 439, 479 EBV-associated lymphomas, 187 Endonuclease, 49, 53, 73, 87, 94f, 98, 127, 129, 132, 147ff, 152, 154, 157, 348, 373f, 463 End-to-end chromosome fusion, 181, 350 Epigenetic modifications, 107, 363, 368f Epigenetic silencing, 485 Episomes, 350, 353 Epistasis group, 215 Epstein-Barr virus (EBV), 351 Exonuclease I (EXO I), 111 Exonuclease III, 129, 152 Extra-chromosomal amplification, 350ff Familial breast cancer, 366, 425, 435 Fanconi’s anemia, 180, 189, 269, 321, 435, 458, 468 F-box protein, 256, 440 FISH: see fluorescence in situ hybridzation Fluorescence in situ hybridzation (FISH), 21, 23ff, 182, 183, 353f, 404, 406 Flap-endonuclease 1, 98, 156 Geminin, 262, 265ff Gene amplification, 7, 343, 346, 352 Glioblastomas, 352, 486 Global genome NER (GG-NER), 48ff H2AX, 179, 181, 268, 348, 427f, 436, 442, 463 Haploinsufficiency, 4, 102, 428 HEC1/Ndc80, 288, 291, 404, 481, 483 Helicases, 49, 202, 257, 430 Helix distortion, 48, 50 506 Hemizygous deletion, 34 Hereditary breast cancer, 180, 433 Hereditary nonpolyposis colon cancer (HNPCC), 6, 14, 85, 93, 95, 99, 100, 105ff, 133, 159, 364, 425 Heterochromatin, 235, 293, 296, 300, 367ff, 374, 376, 381 Hir proteins, 287 Histone deacetylase, 233f, 268, 367, 429, 465 Histone H3, 287, 289, 293, 377, 469 HNPCC: see Hereditary nonpolyposis colon cancer Hodgkin’s lymphoma, 405, 409, 461, 485 Holliday junction (HJ), 178 Homologous recombination (HR), 47, 53, 85, 143, 178, 320f, 377, 436, 462, 492 HP1, 286, 288, 293, 300, 367 HR: see homologous recombination HSRs (homogeneously staining regions), 343 hTERT (human telomerase reverse transcriptase), 33, 233, 320ff, 326f Hydrogen peroxide, 128, 233 Hydroxyurea (HU), 212 Hyper-IgM syndrome (HIGM), 139 Hyperkeratosis, 58, 62 Hypermethylation, 107, 364ff, 373, 381 Hypomethylation, 364, 367ff Hypoxanthine, 127, 131f Hypoxia, 349, 490 ICF syndrome, 370, 373, 375 Immunodeficiency, 190, 369, 429, 432, 461 Ink4a/ARF, 64, 227f, 233, 237f Interferometer-based spectral karyotyping (SKY), 25 Interphase cytogenetics, 22, 27f Index Interphase FISH, 27, 31 Interspersed repeats, 364, 377 Interstrand crosslink repair (ICLR), 53 Intra-chromosomal amplification, 346 Intra-S phase checkpoint, 261, 427, 430, 438ff 467 Inversions, 26, 457, 460 Ionising radiation (IR), 176ff, 316f, 321, 427, 432f, 436, 439, 440ff IR: see ionising radiation Jun/Fos, 154 Juxtacentromeric satellite DNA, 368 Karyotype, 5, 22ff, 34f, 182, 298, 363, 404, 477 Kid, 282 Kinases, 12, 179, 228, 230, 236, 249, 256, 260ff, 289, 291, 299, 315, 317f, 398ff, 428, 431, 433f, 440, 442, 457, 479, 480, 482, 485 Kinesin-related proteins, 282 Kinetochore, 281ff, 299ff, 403ff, 478ff, 493f K-ras, 101, 144, 365 Ku70/80, 35, 177, 183ff, 318, 319, 322, 428, 431, 437, 462 Lesion tolerance, 200, 202 Li-Fraumeni syndrome, 379 LIG4 syndrome, 186 Linear energy transfer (LET), 176 LINES, 23 Lipid peroxidation, 46, 128f LOH: see loss of heterozygosity Loss of heterozygosity (LOH), 5, 35, 64, 99, 322, 328, 366, 380, 462 Lung adenocarcinoma, 157 Lung cancers, 65, 144, 146, 382, 485, 487ff Lymphoid malignancies, 186, 379, 457, 461 Index Lymphoma, 188ff, 298, 325, 328, 380, 432, 461 Mad1, 290, 298, 479ff Mad2, 290, 294, 298, 479ff, 492 MCM: see minichromosome maintenance Mdm2, 228, 231, 236, 268, 404, 466ff Meiosis, 155, 285, 293, 480 Melanoma, 59, 66, 229, 238 Merotelic, 480 Metaphase FISH, 27 Metaphase spreads, 22ff, 32 Metastasis, 3, 58, 105, 326, 364 Methyladenine DNA glycosylase, 131 Methylation, 107, 109, 229, 238, 363ff, 373ff, 382 Microarray, 32, 355 Microcephaly, 55, 57, 59, 62, 432, 437, 484 Microdissection, 6, 27 Micronuclei, 288, 300, 351, 354 Microsatellite instability (MIN) (MSI), 6, 14, 20, 87, 91, 96ff, 132f, 160, 327, 365, 477 Microsatellites, 7, 86, 99, 101, 103f Microtubule inhibitors, 492ff Microtubules, 281ff, 289f, 396, 399, 407, 478ff, 484 MIN: see Microsatellite instability Minichromosome maintenance (MCM), 10, 252ff, 260 Mis6, 287, 291 Mis12, 288 Mis16, 287 Mis18, 287 Mismatch repair (MMR), 6f, 12, 20, 47, 85ff, 133, 141, 145, 159, 327, 364f Missense mutation, 93, 95, 99, 228f, 238, 372, 462, 485f Mitochondria, 128, 142, 144, 150, 185, 443 507 Mitomycin, 47, 427, 432 Mitosis, 144, 199, 253, 258ff, 281ff, 345, 347, 350ff, 369, 377, 394ff, 401, 403, 407ff, 410, 434, 469, 477ff, 489, 492ff Mitotic catastrophe, 397, 407f Mitotic checkpoint, 188, 403, 405, 477ff MLH1/PMS2, 94, 98 MMR: see mismatch repair MMR deficiency, 86, 93, 99, 103, 106, 108 Monopolar attachment, 478 Mosaic variegated aneuploidy (MVA), 484 Mouse embryo fibroblasts (MEFs), 231, 236, 488 Mouse models, 54, 69, 71, 139, 149, 153, 159, 325, 344, 348, 491 Mps1 kinase, 291, 399, 403, 479, 482f Mre11, 103, 110, 181, 188, 316ff, 321, 427, 429, 444, 462ff, 469f MRN (Mre11/Rad50/Nbs1) complex, 103, 178 MSI: see microsatellite instability mTOR, 432 Multicolour FISH, 26, 30, 405 Multiple Adenoma Syndrome, 105 Multipolar mitoses, 406ff Multipolar spindle formation, 182, 393, 405, 410 Mutagenesis, 7, 9ff, 43, 49, 63, 65, 102, 110, 147, 150, 181, 202, 213, 218, 363ff Mutagenic, 127, 128, 131, 133, 145, 151, 155, 200, 214ff, 218, 365 Mutation rate, 3, 8, 11ff, 87, 97, 102, 104, 132, 156, 181, 211, 218, 380, 477 Mutator phenotype, 3, 7ff, 91, 96, 97ff, 102, 203, 363 508 MutL homologues (MLH), 85 MutS homologues (MSH), 85 NADPH-oxidases, 46 Nbs1, 179ff, 188f, 269, 315, 318, 321, 427, 429, 432, 434, 436, 440ff, 458, 463, 467f, 470 Ndc80-complex, 289 Necrosis, 55, 65 NEHJ: see non-homologus endjoining NEIL glycosylases, 129, 149ff Nek2, 398, 403 NER: see nucleotide excision repair Neocarcinostatin, 460, 463 Neocentromeres, 299 Neurodegeneration, 53, 75 Neuropathies, 68, 74 NF-țB, 154 Nijmegen breakage syndrome, 105, 269, 458, 491 NIMA-related kinase, 403 Nipped-B, 301 Nitrosamines, 129 N-myc, 30, 348 Nocodazole, 469, 488ff Non-homologous end-joining (NEHJ), 47, 67, 73, 158, 177, 182ff, 318ff, 330, 346ff, 352, 429, 462 Non-reciprocal translocations, 20, 329, 330 Noxa, 442 NTH1, 129, 143, 147ff Nuclear foci, 180, 348, 427f, 435, 436 Nuclear matrix, 144, 212 Nucleolin, 150 Nucleosome, 268, 286ff Nucleotide excision repair (NER), 12, 45ff, 95, 141, 148, 159, 201, 203, 320 Nude mice, 492 Nuf2, 288, 291 O-6-methylguanine, 208 Okadaic acid, 465 Index Okazaki fragments, 87, 89, 96, 98 Oligodendrocytes, 56, 60f, 67 Oncogenes, 3ff 21, 45, 183, 234, 343, 348, 352, 355, 369, 380 ORC (origin recognition complex), 250ff, 258, 259, 263ff, 270 Osteoporosis, 56, 69, 71 Outer kinetochore, 287f, 290 Oxidative damage, 59, 128, 154 Oxidative stress, 128, 146, 154, 186, 234ff, 324, 491 p16Ink4a, 227, 229ff, 324 p19ARF, 324 p21Cip1, 65, 103, 324, 438, 443, 466, 469, 493 p53, 20, 29, 34, 49f, 65f, 101, 103, 141f, 148, 154, 186ff, 227f, 231ff, 253, 268, 299, 315, 323ff, 344, 347f, 365, 397, 398ff, 404, 407f, 428, 432ff, 442, 444, 466ff, 493 p300, 150, 439 PAD, 210 PALA (N-(phosphonacetyl)-Laspartate), 344 PCNA: see proliferating cell nuclear antigen Pericentric heterochromatin, 293, 492 Pericentric inversions, 26 Pericentromeric heterochromatin, 300, 369, 376 Peripheral nervous system (PNS), 55 Phosphatidylinositol-3’kinase-like kinase (PIKK), 179, 182, 316ff, 432f Photosensitivity, 53, 61, 63 Pif1, 318, 322 Pin1, 439 Point mutations, 7, 11, 327 Pollution, 46 Polycomb group (PcG), 235 Polynucleotide kinase (PNK), 152, 177 Index Polyubiquitination, 439 Postreplication repair (PRR), 200 Pre-replicative complex, 253, 258, 259 Primer extension, 213 Progeria, 62 Programmed cell death, 125, 253 Proliferating cell nuclear antigen (PCNA), 50, 85, 87, 96ff, 111, 135, 138, 142, 148, 152, 157, 212ff, 258, 367, 430 Promoter hypermethylation, 365 Proofreading activity, 86ff, 97f, 155, 159 Proteasome, 263 Protein kinase A (PKA), 397f, 401 Protein kinase C (PKC), 144 Protein serine-threonine phosphatase (PP5), 403, 465 Protein tyrosine kinase (PTK), 434 PUMA, 442 Rad1, 213, 430 Rad5, 215f Rad6, 215f Rad9, 213, 430, 436f Rad17, 213, 315f, 430 Rad21, 294, 296 Rad30, 203ff, 215 Rad50, 181, 316ff, 427, 429, 457, 463ff Rad51, 202, 318, 320, 435 Rad54, 320 Radioresistant DNA synthesis (RDS), 439, 468 Radiosensitivity, 429, 433, 458, 460 Rae1, 487f RAG1/2, 176, 348 Rap1, 313f Ras, 233ff, 324 Rb pathway, 399 Reactive oxygen species (ROS), 45f, 128, 175, 176 RecA, 201, 203, 214 509 Recombination, 13, 23, 53, 102, 105, 109, 125, 139, 155, 176, 178, 186, 189, 201f, 216, 296, 298, 318, 320f, 326, 327, 330, 346, 353, 376ff, 436, 463, 491 Recombination complex RC-1, 298 Replication, 10, 12, 28, 45, 50ff, 63, 85, 87f, 96ff, 110f, 125ff, 133, 135, 138, 142, 148, 151, 175, 176, 179, 182, 184f, 187, 199ff, 210ff, 217, 249ff, 285, 291f, 298, 311, 316, 327, 345, 347, 349ff, 399, 410, 430ff, 439f, 462, 491 - Replication foci, 135, 143, 213, 217 - Replication forks, 10, 176, 179, 200, 212, 217, 257, 430, 439, 462 - Replication initiation factors, 249, 251 - Replication protein A (RPA), 50, 52f, 85, 98, 111, 135, 138, 142, 178, 181, 256, 260, 316f, 323, 430ff - Replication-coupled BER, 148 Replicative DNA polymerases, 10, 86, 135, 152, 155, 199, 206, 210, 213 Replicative senescence, 311, 323 Re-replication, 249, 255, 261ff Respiratory chain, 46 Retinal degeneration, 55, 56, 59, 69 Retinoblastoma protein (pRb), 228, 230 Retrotransposition, 377ff Rev1, 204, 206, 209, 212, 217 Rev3, 204, 209, 215 Rev7, 204, 209 RFC, 50, 252, 430 Ribozyme-mediated inhibition, 492 Rif1, 314, 319 Rif2, 314, 319 510 RING domain, 181, 435 RNA interference (RNAi), 252, 293, 397, 403, 492 RNA polymerase, 48ff, 70, 75, 181, 436 RNA polymerase II, 49, 50, 52, 181 RNA polymerase III, 53 RNase H, 153 Roberts syndrome, 300 Rolling circle amplification, 35 ROS (reactive oxygen species), 46, 52, 59, 67, 74, 128, 146, 151 RPA: see replication protein A S1 nuclease, 298 Satellite DNA, 286, 369, 370, 373ff, 381 Scc1, 291ff Scc3, 291f SCF, 440 Schiff’s base, 145 SCID mice, 187, 189, 326 Seckel syndrome, 349, 432 Securin, 294f, 299 Senescence, 65, 75, 232ff, 311, 314, 318ff, 490 Separase, 294ff Severe combined immunodeficiency (SCID), 188 Single nucleotide polymorphism (SNP), 34 Single nucleotide substitutions, Single strand annealing (SSA), 178 Single strand break (SSB), 128ff, 176 Single-base substitutions, 7, 13, 86 Sister chromatid separation, 284, 291, 293ff, 301, 313, 488, 490 Skp1/Cul1/F-box (SCF), 440 Sliding clamp, 50, 212, 214, 216 Smc1, 179, 291ff, 315, 432, 436, 440f, 467f Smc3, 291f Index Smoking, 65, 146 SMUG1, 133, 135 Somatic hypermutation (SHM), 139, 211 SOS response, 202 Spindle assembly checkpoint, 4, 188, 284, 289f, 294, 298ff, 403, 408 Spindle poles, 395f, 401, 403, 407f Spo11, 176 Sporadic breast cancer, 328 Squamous cell carcinoma (SCC), 58 SSB: see single strand break Stalled replication, 10, 176, 182, 190, 427 Stalled transcription, 48 Stem cells, 11, 69, 365, 368, 377, 380 Strand discrimination, 110 SUMO, 141, 215 Sunlight, 45, 49, 53, 61, 203 Supercoils, 178, 297 Superoxide dismutase (SOD1), 59 Superoxide radical, 128 Survivin, 289 SV40, 33, 231, 255, 344 SV40 T antigen, 255, 344 SWI/SNF, 435 Swi6/HP1, 293, 296 Syntelic attachment, 289, 480 T lymphoma, 185 Tandem DNA repeats, 312, 364, 370, 373, 377 Tankyrase, 313f, 351 Taxanes, 494 Taxol, 480f, 494 T-cell acute lymphoblastic leukaemia (T-ALL), 352 Telomerase, 28f, 184, 232f, 312ff, 330, 348, 437 Telomeres, 20, 178, 183f, 190, 232f, 286, 300, 311ff, 345, 350 - Telomere crisis, 28f Index - Telomere dysfunction, 34, 184, 311, 314ff, 323ff, 347, 350 - Telomere erosion, 20, 233f, 236f, 317, 345, 405, 408 - Telomere fusion, 184f, 190, 318, 320f, 326, 346, 348 - Telomere length homeostasis, 314, 319 - Telomere maintenance, 183, 185, 190, 314, 317ff, 326f, 346, 463 - Telomere repeats, 312, 314, 322 - Telomere shortening, 20, 183f, 312f, 317, 319f, 323ff, 345 - Telomere structure, 311ff Teratocarcinoma, 327 TFIIH, 49ff, 58, 66, 70, 73ff TLS: see translesion synthesis Townes-Brocks syndrome (TBS), 300 Transcription-coupled repair (TCR), 48, 70 Transesterification, 176 Translesion synthesis (TLS), 63, 199ff Translocation, 25, 29, 93, 189f, 264f, 348, 380f, 393, 461 TRF1, 313f, 319 TRF2, 234, 313f, 317ff, 351 Trichothiodystrophy (TTD), 54, 57 Tumour suppressors, 3, 5, 21, 29, 175, 180, 326, 435, 444 Ubiquitin, 52, 65f, 141, 214ff, 228, 251f, 263, 266, 372 - Ubiquitin ligases, 66 Ubiquitination, 214ff, 252, 260, 263, 265f, 294, 400, 404, 439, 468 Ulcerative colitis (UC), 132 Unattached kinetochores, 290, 479, 481f, 484 Uracil DNA glycosylases, 133, 134f, 138ff, 160 511 UV, 24, 45ff, 51ff, 71ff, 156f, 182, 200ff, 212, 215ff, 233, 256, 316, 431f, 439, 460 UV-sensitive syndrome UVs, 54 V(D)J recombination, 176, 178, 182, 186ff, 379, 428, 436 Viral oncoproteins, 29, 232, 326 Werner’s syndrome, 491 Xeroderma pigmentosum (XP), 6, 50, 53f, 58ff, 67, 105, 159, 200, 203, 491 Y-family DNA polymerase, 10, 11, 204, 206, 209ff Zinc finger, 150 Zwint-1, 288 ... relevance to therapy Preface viii Recent years have seen a surge of renewed interest in the role of genome instability in cancer Remarkable progress has been made towards understanding genome instability. .. mutations in genes involved in maintenance of genomic integrity in normal cells Figure lists several genes which when mutated induce genetic instability The mutations have been detected because they... remain to be fully understood In particular, the question of how genome instability impacts on the development of human cancers continues to evoke intense debate Is the observed instability merely