A molecular understanding of homologous recombination in the context of chromatin

Maintaining genome stability and integrity is an essential and challenging cellular process. Homologous recombination (HR) is a major DNA repair pathway while during the highly related meiotic recombination (MR), parental chromosomes exchange and recombine. HR and MR thus play paradoxically distinct roles in maintaining genome stability while promoting genetic diversity. At the heart of HR/MR is the RAD51 recombinase, which forms nucleoprotein filaments to search and pair with homologous DNA sequences, leading to repair or recombination. The function of RAD51 is carefully modulated by partner proteins. Thus far, our mechanistic understanding of HR/MR is limited, especially with partner proteins and in the context of chromatin. This is in part due to the challenges in purifying proteins and associated complexes for structural studies, and in making nucleosomes and arrays. Significantly, RAD51 forms clusters (foci) upon double-strand breaks which disappear after repair. It is unclear what are within these foci and how HR is carried out in cells. I am proposing an ambitious program combining in vitro structural and mechanistic studies with in situ imaging, to provide a molecular understanding of RAD51 and HR and advance our mechanistic understanding of DNA repair, which will also help our understanding of meiotic recombination.