Mismatch2model: Characterization and quantitative modeling of DNA mismatch repair and its role in the maintenance of genomic stability and cancer avoidance DNA mismatch repair (MMR) plays a crucial role in the maintenance of genomic stability. In both bacteria and eukaryotes, the loss of mismatch repair gives rise to a mutator phenotype. In hereditary non-polyposis colon cancer (HNPCC) families, germline mutations in one MSH2, MSH6 or MLH1 allele predispose to cancer of the colon, endometrium, ovary and other organs. HNPCC is the most frequent form of familiar cancer. In the mismatch2model project we adopt and exploit a systems biology approach in which we combine Europe’s expertise in DNA mismatch repair with sophisticated multidisciplinary technology and expertise in quantitative modeling in order to describe this DNA repair process at different levels of complexity. The multidisciplinary consortium will have the following tasks that relate directly to the topics raised in Call HEALTH 2.1.2.5: - Gather quantitative and structural data sets describing the principal steps of DNA mismatch repair - Integrate and analyze structural and functional data obtained from single molecule and bulk studies - Develop mathematical models for single and/or multiple steps of the MMR pathway - Perform analyses at different levels of complexity: from recognition of the mismatch through repairosome assembly to in vivo function - Combine the well-understood MMR E.coli model system with the cancer-protective human system The combination of the individual strengths of the multidisciplinary groups involved in this program ensures that significant progress will be made towards the understanding of this complex process.