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Homology search during homologous recombination: a multi-layered challenge at risk for genomic stability
When Sep 06, 2019
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DNA double-strand breaks are genotoxic lesions whose repair can be templated off an intact DNA duplex through the conserved Homologous Recombination (HR) pathway. HR entails a genome-wide homology search step by the broken molecule. The successful encounter of homology leads the formation of a joint molecule called a “displacement loop” (D-loop). The accuracy of these early steps likely underlie the high fidelity of DNA break repair by HR. Yet, the mechanism of homology search and the metabolism of D-loops in cells remain elusive. To address this fundamental “needle-in-a-haystack” search problem I developed physical assays for the study of D-loop metabolism in S. cerevisiae. It revealed the existence of “multi-invasions” in cells, a byproduct of the homology search process we had postulated. This byproduct is at the basis of a genomic instability and DNA break amplification mechanism that we named “multi-invasions-induced rearrangements” (MIR), with implications for the formation of complex chromosomal rearrangements observed in human. Several proteins inhibit MIR, including conserved HR-related helicases such as Mph1 (human FANCM), Sgs1-Top3-Rmi1 (BLM-TOPO3-RMI1/2), and Srs2. Physical examination of perfectly homologous D-loop levels in cells revealed that the majority are reversed by these proteins. In addition to guard against MIR, this constitutive D-loop reversal may enabled exhaustive and stringent sampling of the genomic space, and thus be an integral component of homology search. Building upon these methodologies and findings, the goal of my future lab will be to investigate the interplay between events occurring at the chromosomal scale (structure and dynamics) and at the molecular scale (homology search and joint molecules metabolism) by combining experiments and computational modelling. A first research axis, in the continuity of my previous work, will be directed at the development of a quantitative framework of homology search in vegetative cells. A second research axis will aim at defining the elusive HR-driven phenomenon of homolog bias and crossover patterning underlying homologs pairing during meiosis.

Contact : Didier Auboeuf