This integrated project focuses on unravelling mechanisms of DNA damage response and repair, an area with a major impact on human health, notably cancer, immunodeficiency, other ageing related-diseases and inborn disorders. The proposal 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. Translation of the results that we obtain is expected to contribute to an improved quality of life through (1) possible identification of genetic markers for assessment of susceptibility to occupational hazards and disease, (2) discovery of promising targets for therapy, (3) improved diagnostic and prognostic procedures for genetic disorders, (4) 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, who may become the leaders of tomorrow. Approach: The pleiotropic effects 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. To better understand the function and impact of DNA damage response and repair systems in living organisms, 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 effects 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 identified defects in DNA damage response and repair mechanisms and use our clinical contacts to screen for new disorders.