Cancer Research - Europa

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