Heterochromatic repeat clustering imposes a physical barrier on homologous recombination to prevent chromosomal translocations

I Mitrentsi; J Lou; A Kerjouan; J Verigos; B Reina-San-Martin; E Hinde; E Soutoglou

Journal article

Heterochromatic repeat clustering imposes a physical barrier on homologous recombination to prevent chromosomal translocations

I Mitrentsi, J Lou, A Kerjouan, J Verigos, B Reina-San-Martin, E Hinde, E Soutoglou

Molecular Cell | Published : 2022

DOI: 10.1016/j.molcel.2022.03.033

Abstract

Mouse pericentromeric DNA is composed of tandem major satellite repeats, which are heterochromatinized and cluster together to form chromocenters. These clusters are refractory to DNA repair through homologous recombination (HR). The mechanisms by which pericentromeric heterochromatin imposes a barrier on HR and the implications of repeat clustering are unknown. Here, we compare the spatial recruitment of HR factors upon double-stranded DNA breaks (DSBs) induced in human and mouse pericentromeric heterochromatin, which differ in their capacity to form clusters. We show that while DSBs increase the accessibility of human pericentromeric heterochromatin by disrupting HP1α dimerization, mouse p..

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University of Melbourne Researchers

Jieqiong Lou Author

Elizabeth Hinde Author

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Grants

Awarded by Laboratoire d'Excellence INRT

Funding Acknowledgements

We thank K. Meaburn, F. Erdel and Matthias Altmeyer for critical reading of the manuscript and members of the Soutoglou laboratory for comments; F. Erdel for the dCas9-EGF-VPR plasmid; Y.M. Yamashita for the D1-GFP plasmid; C. Vourch for the DBD-TRIM-EGFP plasmid; D. Stroud for the mKate2 plasmid; J. Jimenez Sainz for the mCherry-BRCA2 plasmid; R. Greenberg for the FlagTRF1-Fok1 plasmid; D. Durocher for the PALB2-GFP plasmid; H. van Attikum for the mCherry-XRCC4 plasmid; S. Daujat for the MEF cell lines; A. Nussenzweig for the BRCA1 antibody; the IGBMC Imaging Center for support; and the Biological Optical Microscopy Platform, University of Melbourne, for enabling access to the Olympus FV3000 confocal laser scanning microscope. I.M. was supported by LabEX INRT and by the Foundation ARC for the research against cancer. The E.S. laboratory was supported by the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation program (ERC-2015-COG-682939) and by ANR-10-LABX-0030-INRT, managed by the Agence Nationale de la Recherche under the program Investissements d'Avenir, labeled ANR-10-IDEX-0002-02, and the Academy of Medical Sciences (AMS). A.K. and J.L. were supported by Australian Research Council (ARC) discovery projects (DP180101387 and DP210102984). E.H. was supported by a National Health and Medical Research Council (NHMRC) career development fellowship (APP1124762) and an ARC future fellowship (FT200100401).