Temporal and spatial uncoupling of DNA double strand break repair pathways within mammalian heterochromatin

Tsouroula, Katerina, Furst, Audrey, Rogier, Melanie, Heyer, Vincent, Maglott-Roth, Anne, Ferrand, Alexia, Reina-San-Martin, Bernardo and Soutoglou, Evi (2016) Temporal and spatial uncoupling of DNA double strand break repair pathways within mammalian heterochromatin. Molecular Cell, 63 (2). pp. 293-305. ISSN 1097-2765

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Repetitive DNA is packaged into heterochromatin to maintain its integrity. We use CRISPR/Cas9 to induce DSBs in different mammalian heterochromatin structures. We demonstrate that in pericentric heterochromatin, DSBs are positionally stable in G1 and recruit NHEJ factors. In S/G2, DSBs are resected and relocate to the periphery of heterochromatin, where they are retained by RAD51. This is independent of chromatin relaxation but requires end resection and RAD51 exclusion from the core. DSBs that fail to relocate are engaged by NHEJ or SSA proteins. We propose that the spatial disconnection between end resection and RAD51 binding prevents the activation of mutagenic pathways and illegitimate recombination. Interestingly, in centromeric heterochromatin, DSBs recruit both NHEJ and HR proteins throughout the cell cycle. Our results highlight striking differences in the recruitment of DNA repair factors between pericentric and centromeric heterochromatin and suggest a model in which the commitment to specific DNA repair pathways regulates DSB position.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 06 Jul 2020 10:25
Last Modified: 26 Mar 2021 16:01
URI: http://sro.sussex.ac.uk/id/eprint/92311

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