Service Communautaire d'Information sur la Recherche et le Développement - CORDIS

Periodic Report Summary 1 - MEIOREP (Interplay between the program of DNA replication and meiotic recombination)

The control of genome duplication is critical for cell growth and proliferation. Errors in DNA synthesis have been linked to many human diseases, and defects in genome maintenance have been shown to contribute to cancer progression. In eukaryotes, replication initiation occurs at sites distributed throughout the chromosomes known as origins. Changes in the pattern, or program, of replication have been observed in development and differentiation as well as in pathologies, but it remained unknown whether these alterations have consequences on cellular function. Using the fission yeast Schizosaccharomyces pombe, an excellent eukaryotic model for studying cell cycle progression and DNA replication, we have recently shown that the program of replication is a major regulator of the sites of double-strand break (DSB) formation during meiosis, which is central to the exchange of genetic material during sexual reproduction. Our findings provided the first demonstration of the functional importance of the organization of genome duplication. Taking advantage of our system, we are combining the powerful yeast genetic model with molecular biology, live-cell imaging, and single-molecule methodologies to determine the molecular mechanisms that couple the crucial processes of DNA replication and meiotic recombination.

During the first part of the research period, we have made important progress in our aims. First, we have implemented new approaches that serve as the foundation for our studies, including a chemical genetic procedure for inducing synchronous meiosis at physiological temperatures and the development of drug-compatible, temperature-controlled microfluidic devices for live-cell imaging. Second, we have established methods that allow us to specifically modulate distinct steps in replication initiation, and we are assessing their roles in meiotic recombination both genome-wide and in individual cells. Third, we have evaluated the importance of chromatin structure and modification in mediating in the link between replication initiation and meiotic DSB formation. Fourth, we have engineered strains to investigate whether the duplication of a region of the genome is required for DSB formation within that region. Finally, we have developed single-molecule techniques for analyzing replication and recombination along individual chromosomes. Taken together, our work has given rise to promising initial findings and is poised to generate exciting results that will elucidate the crosstalk between replication and recombination.

The initial period of the Career Integration Grant (CIG) has allowed me to establish my laboratory, which now consists of an international team of seven researchers with diverse backgrounds. Prior to the CIG grant, I was awarded a permanent research position by the National Center for Scientific Research (CNRS) in France. My group actively contributes to the scientific life of our institute and is well-integrated at the regional and national levels, both as a participant in and organizer of meetings and workshops. Moreover, we have established national and international collaborations that provide complementary competencies for our work. The first CIG period has allowed my laboratory to build a strong foundation that puts us in the best possible position to make rapid progress in our studies.

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Life Sciences