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Mechanism of homology search expansion during recombinational DNA break repair in Saccharomyces cerevisiae.
Mol Cell, 84(17):3237-3253.e6.
Homology search is a central step of DNA double-strand break (DSB) repair byhomologous recombination (HR). How it operates in cells remains elusive. Wedeveloped a Hi-C-based methodology to map single-stranded DNA (ssDNA) contactsgenome-wide in S. cerevisiae, which revealed two main homology search phases.Initial search conducted by short Rad51-ssDNA nucleoprotein filaments (NPFs) isconfined in cis by cohesin-mediated chromatin loop folding. Progressive growth ofstiff NPFs enables exploration of distant genomic sites. Long-range resectiondrives this transition from local to genome-wide search by increasing theprobability of assembling extensive NPFs. DSB end-tethering promotes coordinatedsearch by opposite NPFs. Finally, an autonomous genetic element on chromosome IIIengages the NPF, which stimulates homology search in its vicinity. This workreveals the mechanism of the progressive expansion of homology search thatis orchestrated by chromatin organizers, long-range resection,end-tethering, and specialized genetic elements and that exploits the stiff NPFstructure conferred by Rad51 oligomerization.
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