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"Meiotic recombination: How, where and why? Mechanisms and Implications"

Final Report Summary - HOTMEIOSIS (Meiotic recombination: How, where and why? Mechanisms and Implications)

The research project, HOTMEIOSIS, was aimed to decipher basic molecular mechanisms responsible for recombination between chromosomes during meiosis.
In most sexually reproducing species, including mice, which is our model organism for this project, parental chromosomes exchange genetic information during meiosis. These exchanges are essential for fertility and contribute to increasing the genetic diversity at each generation.
Previous studies in mice have shown that two key proteins, PRDM9 and SPO11, play important roles in the initiation step of meiotic recombination. The approaches we have developed have allowed to understand their mode of action and to identify other proteins directly involved in this process.
By combining, mouse genetics, molecular biology, and genomics, we have demonstrated that PRDM9 acts by generating a chromatin substrate with specific and essential histone modifications. We have identified the binding sites of PRDM9 in the mouse genome. We have explored and monitored PRDM9 diversity in wild mice, showing an extraordinarily high level of polymorphism, and predicting highly variable binding sites in the genome during evolution. These PRDM9 binding sites are the genomic sites where SPO11 acts and generates DNA breaks to promote exchanges between chromosomes. We have searched for and discovered a protein that interacts with SPO11 and that we named TOPOVIB-like. The existence of this protein was hypothesized many years ago but never identified. Its discovery is a major breakthrough in the field as we now have the complete core catalytic complex for this molecular reaction and because the identification of TOPOVIB-like establishes a strong evolutionary link between these proteins involved in meiosis and another family of proteins called DNA topoisomerases involved in the regulation of DNA topology.
Altogether these advances allow defining important concepts underlying the three major steps of the initiation of meiotic recombination: the specification of genomic sites by PRDM9, the interaction between these sites and protein complexes which assembly is coordinated by chromosome structure, the activation of the catalytic activity of SPO11/TOPOVIB-like to generate DNA breaks. These sophisticated interactions are essential for the stability and hereditary transmission of the genome at each generation as they ensure that the DNA breaks generated are faithfully repaired and provide the chromosomal exchanges required for gamete formation.