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Cohesin regulates homology search during recombinational DNA repair

Aurele Piazza, Helene Bordelet, Agnes Dumont, Agnes Thierry, Jerome Savocco, Fabien Girard, and Romain Koszul (2020)

Biorxiv.

Homologous recombination (HR) is a ubiquitous DNA double-strand break (DSB) repair mechanism that promotes cell survival. It entails a potentially genome-wide homology search step, carried out along a conserved RecA/Rad51-ssDNA nucleoprotein filament (NPF) assembled on each DSB ends. This search is subdued to NPF-dsDNA collision probability, dictated in part by chromatin conformation. In contrast to the extensive knowledge about chromatin composition and mobility changes elicited by the DNA damage checkpoint (DDC), whether, how, and to which extent a DSB impacts spatial chromatin organization, and whether this organization in turns influences the homology search process, remains ill-defined. Here we characterize two layers of spatial chromatin reorganization following DSB formation in S. cerevisiae. While cohesin folds chromosomes into cohesive arrays of 10-20 kb long chromatin loops as cells arrest in G2/M, the DSB-flanking regions locally interact in a resection- and 9-1-1 clamp-dependent manner, independently of cohesin and HR proteins. This local structure blocks cohesin progression, constraining the extending NPF at loop base. Functionally this organization promotes side-specific cis DSB-dsDNA interactions that scales with loop expansion span, and provides a kinetic advantage for identification of intra- over inter-chromosomal homologies. We propose that cohesins regulate homology search by promoting cis dsDNA over-sampling, both upon loop expansion-coupled unidimensional dsDNA scanning, NPF trapping, and chromosome individualization, largely independent of their role in sister chromatid cohesion.
https://www.biorxiv.org/content/10.1101/2020.12.17.423195v1

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