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 a lso 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. 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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. 9 8 7 6 5 4 3 2 1 springeronline.com TABLE OF CONTENTS Preface vi List of Contributors ix Part 1. The Problem of Genome Instability 1.1. The Multiplicity of Mutations in Human Cancers 3 Ranga N. Venkatesan and Lawrence A. Loeb 1.2. Monitoring Chromosome Rearrangements 19 Michael R. Speicher Part 2. DNA Repair and Mutagenesis 2.1. Nucleotide Excision Repair and its Connection with Cancer and Ageing 45 Jaan-Olle Andressoo, Jan H.J. Hoeijmakers and Harm de Waard 2.2. DNA Mismatch Repair and Colon Cancer 85 Giancarlo Marra and Josef Jiricny 2.3. Base Excision Repair 125 Lisiane B. Meira, Nicholas E. Burgis and Leona D. Samson 2.4. Genomic Instability in Cancer Development 175 Penny A. Jeggo 2.5. Translesion Synthesis and Error-Prone Polymerases 199 Catherine M. Green and Alan R. Lehmann vi Table of Contents Part 3. Cell Cycle Progression and Chromosome Aberration 3.1. The INK4A/ARF Network – Cell Cycle Checkpoint or Emergency Brake? 227 Ana Gutierrez del Arroyo and Gordon Peters 3.2. DNA Replication and Genomic Instability 249 Wenge Zhu, Tarek Abbas and Anindya Dutta 3.3. The Dream of every Chromosome: Equal Segregation for a Healthy Life of the Host 281 Tomohiro Matsumoto and Mitsuhiro Yanagida 3.4. Telomere Structural Dynamics in Genome Integrity Control and Carcinogenesis 311 Roger A. Greenberg and K. Lenhard Rudolph 3.5. Gene Amplification Mechanisms 343 Michelle Debatisse and Bernard Malfoy 3.6. DNA Methylation and Cancer-Associated Genetic Instability 363 Melanie Ehrlich 3.7. Deregulation of the Centrosome Cycle and the Origin of Chromosomal Instability in Cancer 393 Wilma L. Lingle, Kara Lukaswiewicz and Jeffrey L. Salisbury Part 4. Genome Integrity Checkpoints 4.1. Mammalian DNA Damage Response Pathway 425 Zhenkun Lou and Junjie Chen 4.2. ATM and Cellular Response to DNA Damage 457 Martin F. Lavin, Sergei Kozlov, Nuri Gueven, Cheng Peng, Geoff Birrell, Phillip Chen and Shaun Scott 4.3 Mitotic Checkpoint, Aneuploidy and Cancer 477 Tim J. Yen and Gary D. Kao Index 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. viii Preface 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 Institute of Technology Room 56-235 77 Mass Avenue Boston, MA 02139 USA