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DNA Repair<br />
DNA Damage Response<br />
and Repair Mechanisms<br />
Summary<br />
This project focuses on unravelling the mechanisms of DNA<br />
damage response and repair, an area with a major impact<br />
on human health, notably cancer, immunodefi ciency, other<br />
ageing related-diseases and inborn disorders. The project<br />
brings together leading groups with multi-disciplinary and<br />
complementary expertise to cover all pathways impinging<br />
upon genome stability, ranging from molecules to mouse<br />
models and human disease.<br />
The main objective is to obtain an integrated perception of<br />
the individual mechanisms, their complex interplay and<br />
biological impact, using approaches ranging from structural<br />
biology to systems biology. The translation of the results<br />
that we obtain is expected to contribute to an improved<br />
quality of life through:<br />
• possible identifi cation of genetic markers for assessment<br />
of susceptibility to occupational hazards and disease;<br />
• discovery of promising targets for therapy;<br />
• improved diagnostic and prognostic procedures for<br />
genetic disorders;<br />
• early diagnosis and prevention of cancer and other<br />
ageing-related diseases. We have also included a strong<br />
training component in the project to invest in young<br />
talented students for the future.<br />
To understand the function and impact of DNA damage<br />
response and repair systems in living organisms better, we<br />
will take full advantage of our existing unique and extensive<br />
collection of models (mutant yeast cells and mice), and engineer<br />
and analyse new mutants impaired in genome stability.<br />
The rapid growth in genomic and proteomic technologies<br />
will be exploited to identify novel genes involved in genome<br />
surveillance. We will use bioinformatics and high-throughput<br />
systems for analysis of gene expression, and proteomics to<br />
identify putative functions of such genes and their proteins,<br />
as well as similar global genome analytical tools to identify<br />
interactions with, and eff ects on, other cellular processes.<br />
The ‘drugability’ of potential targets to improve anti-cancer<br />
therapy will be tested in collaboration with SMEs. Through<br />
existing contacts with clinicians we will continue to analyse<br />
patients with previously identifi ed defects in DNA damage<br />
response and repair mechanisms, and use our clinical contacts<br />
to screen for new disorders.<br />
28<br />
Keywords | DNA damage | genome (in)stability | cancer pre-disposition | genomics | proteomics | mouse models |<br />
Background<br />
The pleiotropic eff ects, inherent to the time-dependent erosion<br />
of the genome and the complexity of the cellular responses<br />
to DNA damage, necessitate a comprehensive, multi-disciplinary<br />
approach, which ranges from molecule to patient. At the<br />
level of structural biology and biochemistry, individual components<br />
and pathways will be analysed to identify new<br />
components and clarify reaction mechanisms. The interplay<br />
between pathways and cross talk with other cellular processes<br />
will be explored using both biochemical and cellular assays.<br />
Aim<br />
To get to grips with the vast problem of DNA damage, an<br />
integrated, multidisciplinary approach is imperative. The level<br />
of understanding of many individual pathways has strongly<br />
increased through worldwide research in which European<br />
teams have played a prominent role. The main questions and<br />
challenges ahead are:<br />
• moving from understanding distinct pathways towards the<br />
complex interplay between the various genome stability<br />
systems putting these pathways in an integrated cellular<br />
context, perfectly fi tting into the concept of integrated<br />
projects;<br />
• insight into the clinical impact of the systems individually<br />
and collectively from the cellular level to that of intact<br />
organisms, and extending to the human population;<br />
• translation of this knowledge into practical applications<br />
in terms of improved diagnosis, eff ective therapy and<br />
prevention or postponement of diseases associated with<br />
the functional decline of the genome.<br />
Expected results<br />
• A detailed understanding of the biochemical mechanism<br />
of DNA repair and checkpoint pathways.<br />
• Insight into the cellular functioning and consequences of<br />
defects in one of the genome surveillance pathways.<br />
• Identifi cation of new components of DNA damage<br />
response pathways.<br />
• Extension of knowledge from model organisms to<br />
humans. This will be accomplished by the investigation<br />
of patients and cells from patients suff ering from genome<br />
instability, cancer predisposition and premature ageing<br />
syndromes, and also by an extensive comparison of<br />
mouse mutants with human diseases involving genome<br />
instability, cancer predisposition and premature ageing.<br />
CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME