Project description
Molecular insight into chromosomal recombination during meiosis
The formation of DNA double strand breaks (DSBs) during meiotic division is necessary for recombination and fertility. However, meiotic DSBs pose a major challenge for genomic integrity. The EU-funded DSBSunrise project will investigate the hypothesis that this process is tightly regulated to ensure efficient DNA DSB repair by homologous recombination. Researchers will provide topological insight into the process and identify the genomic sites where DSBs take place. They will also study how DSB sites interact with structural components of the repair mechanism, offering fundamental knowledge on the complex process of meiotic chromosomal recombination.
Objective
At the onset of prophase of the first meiotic division, meiotic cells undergo complex molecular events with the induction of several hundred DNA double-strand breaks. These DNA breaks are required because they initiate recombination between homologous chromosomes and to allow chromosome segregation during meiosis. They are essential for fertility. However, they represent a major challenge for genome integrity.
It is thought that meiotic DNA break formation is under tight control to ensure that all breaks are properly repaired to maintain genome integrity. But how this control implemented is unknown.
We postulate that three critical steps take place to ensure meiotic DNA break formation at the right time, right place, and right frequency. We will test this hypothesis by addressing in mice the three following questions:
Q1: We will ask whether a homology-sensing process brings homologous chromosomes in spatial proximity before DNA break formation to improve DSB repair efficiency and avoid topological conflicts. If this is the case, we will determine the molecular mechanism.
Q2: We will determine whether the genomic sites undergoing DNA breakage interact with structural components of chromosome axes before break formation, and how. This interaction is predicted to be necessary for proper DSB repair.
Q3: We will determine how DNA cleavage is activated. We will do this through in vitro reconstitution of meiotic DSB formation.
Answering these key questions will be possible by using in vivo and in vitro approaches. We will pioneer in vitro meiotic differentiation of mouse embryonic stem cells to overcome the current limitations for identifying novel components and interactions.
We will thus decipher how a molecular machinery that has evolved from a DNA type II topoisomerase family has been selected and modified to promote a complex reaction initiated by DNA cleavage at multiple sites along chromosomes followed by their repair by homologous recombination.
Fields of science
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
75794 Paris
France