Double-strand breaks (DSB) constantly challenge the integrity of the cellular genome and are important contributors to cancer and genetic diseases. Repair of damaged DNA is a dynamic process that requires careful orchestration of a multitude of enzymes and chromatin constituents that are organized into centers (foci). The outgoing laboratory recently developed powerful methods to explore the dynamics of focus assembly/disassembly in vivo. Using these techniques, I will explore one of the most intriguing steps of homologous recombination: the search for homology. During homologous recombination, the broken DNA searches for intact homologous dsDNA within the entire genome. To elucidate when and how the process of homology search occurs in vivo, I will visualise the movement of a donor and an acceptor sequence, as well as recombination factors, before, during and after double strand break repair. I will take advantage of the elegant yeast genetic system and explore the effects of targeted mutations in key enzymes involved in this process. In the return laboratory, I will to transpose the assay developed in the outgoing laboratory in mammalian cells. With the aid of the Marie Curie fellowship, I propose to spend my post-doctoral period to evolve from single molecule approaches in vitro to genetics and in vivo systems involving multiprotein complexes.
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