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Investigating the interplay between DNA replication and meiotic recombination

Abstract : DNA replication is a highly conserved and regulated step of the cell cycle. Defects in genome duplication have severe consequences for cell proliferation and have been linked to different pathologies, including cancer. Replication initiates at discrete sites along the chromosomes known as origins. For a population of cells, the program of replication is defined by the distribution and activation of origins across the genome. However, cells within the same population display plasticity in origin usage, and the subset of origins activated during S-phase varies from one cell cycle to the next. While changes in the replication program have been observed during development and differentiation as well as in cancer, the functional importance of these alterations remained unknown. Our laboratory previously demonstrated in the fission yeast that the program of origin selection during pre-meiotic S phase regulates the sites of double-strand break (DSB) formation during meiosis, providing the first evidence for the functional consequences of genome-wide changes in origin usage. Building on this work, my thesis takes two approaches to investigate the crosstalk between genome duplication and meiotic recombination, using the fission yeast Schizosaccharomyces pombe as a model system. First, we explored the impact of chromosomal organization on the program of DNA replication and meiotic recombination. To this end, we engineered chromosomal rearrangements that exchange the positions of replication domains with different efficiency and timing characteristics. Our results demonstrated that this induced local changes in origin efficiency near the endpoints of the rearranged region during both mitotic and pre-meiotic S phase. Interestingly, while genome-wide analysis of the DSB profile showed alterations near the rearranged ends, these differences did not reflect the changes in origin usage. This unexpected finding suggests a complex regulation of DSB formation during meiosis that hints at a potential role for chromosomal context in this process. In addition, we aimed to investigate the steps in DNA replication that are important for promoting DSB formation. Specifically, we focused on evaluating whether the replication machinery must progress through a DSB site before breaks are formed or whether origin activation is sufficient to induce nearby DSBs. For these studies, we constructed and characterized a system for inducing a replication fork barrier during pre-meiotic S phase. Taken together, my thesis work provides new directions for investigating the interplay between chromosomal organization, DNA replication and meiotic recombination.
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  • HAL Id : tel-03678984, version 1

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Lilian Lanteri. Investigating the interplay between DNA replication and meiotic recombination. Genetics. Université Rennes 1, 2018. English. ⟨NNT : 2018REN1B002⟩. ⟨tel-03678984⟩

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