BENZON SYMPOSIUM No. 52 Cellular Responses to DNA Damage Primary tabs

August 22-25, 2005 – Copenhagen, Denmark

Organizing committee: Jiri Bartek (Copenhagen), Jiri Lukas (Copenhagen), Jan Hoeijmakers (Rotterdam) and Arne Svejgaard (Copenhagen) Invited speakers and chairmen: Robert T. ABRAHAM, USA – Alan D. d’ANDREA, USA – Jiri BARTEK, Denmark – Vilhelm BOHR, USA – Jean-Christophe Bourdon, UK – Junjie CHEN, USA – Titia DE LANGE, USA – John F. X. DIFFLEY, UK – Marco FOIANI, Italy – Jean GAUTIER, USA – Thanos D. HALAZONETIS, USA – Jan H. J. HOEIJMAKERS, The Netherlands – Stephen P. JACKSON, UK – Penelope A. JEGGO, UK – Roland KANAAR, The Netherlands – Michael B. KASTAN, USA – Martin LAVIN, Australia – David M. LIVINGSTON, USA – Jiri LUKAS, Denmark – André NUSSENZWEIG, USA – John H. J. PETRINI, USA – Yosef SHILOH, Israel – Geoffrey M. WAHL, USA – Stephen C. WEST, UK

Synopsis: Every fruitful and rapidly developing field of biomedical research eventually reaches a stage when further development requires integration with knowledge on the closely related topics, and interdisciplinary coordination of basic aspects with their potential applications in medicine. Such a stage has now been reached by the area of research focusing on the molecular mechanisms that monitor and ensure genomic integrity, prevent genetic diseases, and underlie responses to therapeutic modalities such as radiation and chemotherapy.

The unifying theme of these mechanisms, the so-called genome integrity checkpoints activated in response to genotoxic stress encompasses the sensors of DNA damage, the activated signalling cascades, and the downstream targets within the cell-cycle and DNA repair machineries. Furthermore, key components of these pathways are often deregulated or mutated in genetic diseases including cancer and premature aging, and there is a growing optimism (supported by emerging evidence) in the biomedical research community that these mechanisms and defects may represent novel therapeutic targets. A major complicating issue in this multidisciplinary field has been the widely spread interests of researchers whose work inevitably deals only with a particular aspect of the DNA damage response, such as very diverse model organisms, different aspects of the pathways or their targets, and different ’distance’ between the very basic versus clinical research. On the other hand, the pathways that respond to DNA damage are very highly conserved in evolution, and the key genes and proteins that regulate and carry out this cellular response feature prominently in both the basic biological phenomena and disease-predisposing defects. This unifying concept highlights the great benefit of a closer dialog, exchange of views and ideas between scientists working on these different facets of the same biological response for global efforts to further advance and exploit this accumulating knowledge.

It seems that the best way to promote the field is to gather internationally recognized leaders working on these analogous mechanisms in different eukaryotes (from yeast to men), on different levels of the response (from the DNA lesion recognition to cell cycle arrest and DNA repair), and on emerging medical and pharmacological applications. This Benzon Symposium should help demystify the optical illusion of the seemingly wide distances between scientists who, in fact, all share an interest in the same biological response, carried out by the same molecular network. At the same time, this dialog would open enormous possibilities of ‘cross-polination’ between these closely related topics, and accelerate the pace of basic discoveries as well as their applications in medicine.

Scientific programme:

J. Bartek: Introduction
Session I: Cell cycle checkpoints Chair: Jiri Lukas & Michael B. Kastan
S. P. Jackson: Molecular and functional analysis of the DNA-damage response
J. Chen: MDC1 Maintains Genomic Stability by Participating in the Amplification of ATM-Dependent DNA Damage Signals
J. F. Diffley: DNA Replication Control and Genome Stability
M. Foiani: Cell cycle checkpoints and the integrity of replicating chromosomes
E. S. Kats: Mutations in S. cerevisiae chromatin assembly factors CAF-I and RCAF cause replication-dependent DNA damage which is reliant on different checkpoint pathways for suppression (Poster No. I-1) V.
Costanzo: ATM and ATR prevent double-strand break accumulation during chromosomal DNA replication by promoting Mre11 dependent repair and restart of damaged replication forks (Poster No. I-2)
R. Medema: H Polo-like kinase-1 regulates checkpoint adaptation and recovery (Poster No. I-3)
V. A. J. Smits: DNA damage-induced dissociation of Chk1 from chromatin (Poster No. I-4)
J. H. J. Petrini: The cellular DNA damage response: Diverse functions converge J. Bartek: DNA damage checkpoints: Mechanisms and role in tumorgenesis

Session II: ATM AND RELATED KINASES Chair: John H. J. Petrini & Stephen P. Jackson
Y. Shiloh: New insights into ATM-mediated responses to DNA damage
M. B. Kastan: Signalling to and from ATM after DNA damage
R. T. Abraham: Tumor-Associated Replication Stress and the Cellular Response to Anticancer Agents
M. Lavin: Spinocerebellar ataxia, oxidative stress and DNA damage response Jean Gautier: A two-step mechanism of ATM activation
D. Cortez: Multiple ATRIP functional domains regulate ATR localization and activity (Poster No. II-1)
K. Cerosaletti: An active role for nibrin in the kinetics of Atm activation following irradiation (Poster No. IIIA-1)

Session III: TRANSDUCTION AND REPAIR OF DNA DAMAGE Chair: Penelope A. Jeggo & Jean Gautier
D. M. Livingston: Searching for a Specific Contribution by Loss of BRCA1 Function to Breast Cancer Development
S. C. West: Making and Breaking Recombination Intermediates
T. D. Halazonetis: 53BP1: Emerging tumour suppressor involved in early stages of DNA damage signalling
G. M. Wahl: Mouse bites dogma: Mouse models provide new insights into the mechanisms that control the p53 stress response pathway

Session IV: FROM THE TEST TUBE TO LIVE CELL IMAGING Chair: Titia De Lange & Yosef Shiloh
R. Kanaar: Dynamic organization of genome maintenance proteins in vitro and in vivo
J. Lukas: DNA damage checkpoints and their intra-nuclear dynamics
L. Ström: Structural Maintenance of Chromosome, SMC-proteins and their role in repair of and response to DNA damage (Poster No. IIIB-0)
J. A. Downs: Modulation of chromatin during DNA double-strand break repair (Poster No. IIIB-1)
M. Stucki: MDC1/NFBD: The primary g-H2AX recognition module of higher eukaryotes (Poster No. IIIB-2)
M.S. Meyn: Human TRF2, TRF1 and TIN2 rapidly associate with genomic double-strand breaks: An novel early DNA damage response (Poster No. IV-1)
A. Nussenzweig: Changes in Chromatin Structure and Mobility in Living Cells at Sites of DNA Double-strand Breaks

P. Jeggo: Hereditary Disorders conferred by Defective DNA Damage Responses
T. De Lange: Protection and maintenance of human chromosome ends
A. D. D’Andrea: The Fanconi Anemia/BRCA pathway in the DNA damage response
V. Bohr: DNA Repair deficiencies in Human Premature Aging
J.-C. Bourdon: New isoforms of p53 and their role in the DNA damage response
F. Esashi: Dynamic regulation of BRCA2 for Recombinational Repair (Poster No. V-1)
T. Helleday: Repair at DNA replication forks and a treatment for BRCA2 tumours (Poster No. V-2)
M. Laiho: NPM and PML interact in DNA damaged cells (Poster No. V-3)
J. H. J. Hoeijmakers: Nucleotide excision repair in cancer and ageing
J. H. J. Hoeijmakers: Concluding remarks

Abstracts (pdf)