Orateur
Description
Homologous recombination (HR) is a conserved DNA repair mechanism that uses an intact DNA molecule as a template to mend double-strand breaks (DSBs) and single-stranded gaps, ensuring genomic stability. The accurate search and choice of an homologous donor is of prime importance for HR fidelity, as repairing using non-allelic repetitive sequences can lead to structural variations. Multiple mechanisms involved in the homology search mitigate this risk, but they remain incompletely characterized.
My PhD project aims to elucidate the molecular controls governing donor selection during HR. To this end, I developed a computational model of the HR pathway in S. cerevisiae that integrates stochastic parameters for complex formation, disruption rates, protein binding on single-stranded DNA, and chromatin accessibility. Guided by quantitative experimental data, the model simulates thousands of virtual cells, each generating metrics such as first passage times for the homology search, numbers of D-loops formed or disrupted, and high-resolution two-dimensional chromatin contact maps.
By aggregating these outputs, the framework provides robust population-level insights, correlates input parameters with HR outcomes, and facilitates direct comparisons with experimental data. Ultimately, this predictive model will help quantify the roles of specific factors in ensuring HR efficiency and fidelity, with ongoing experimental validations further refining our understanding of homologous donor selection.