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Nucleic Acids Res. 2015 Sep 18;43(16):7931-44. doi: 10.1093/nar/gkv722. Epub 2015 Jul 22.

SETDB1, HP1 and SUV39 promote repositioning of 53BP1 to extend resection during homologous recombination in G2 cells.

Author information

1
University of Sussex Genome Damage and Stability Centre, East Sussex, BN19RQ, UK.
2
Division of Genome Biology, National Cancer Centre Japan Research Institute, Tokyo, 104-0045, Japan.
3
Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, 852-8523, Japan.
4
University of Sussex Genome Damage and Stability Centre, East Sussex, BN19RQ, UK Department of Biology, School of Sciences and Engineering, The American University in Cairo, New Cairo, 11835, Egypt.
5
University of Sussex Genome Damage and Stability Centre, East Sussex, BN19RQ, UK p.a.jeggo@sussex.ac.uk.

Abstract

Recent studies have shown that homologous recombination (HR) requires chromatin repression as well as relaxation at DNA double strand breaks (DSBs). HP1 and SUV39H1/2 are repressive factors essential for HR. Here, we identify SETDB1 as an additional compacting factor promoting HR. Depletion of HP1, SUV39, SETDB1 or BRCA1 confer identical phenotypes. The repressive factors, like BRCA1, are dispensable for the initiation of resection but promote the extension step causing diminished RPA or RAD51 foci and HR in irradiated G2 cells. Depletion of the compacting factors does not inhibit BRCA1 recruitment but at 8 h post IR, BRCA1 foci are smaller and aberrantly positioned compared to control cells. BRCA1 promotes 53BP1 repositioning to the periphery of enlarged foci and formation of a devoid core with BRCA1 becoming enlarged and localized internally to 53BP1. Depletion of the compacting factors precludes these changes at irradiation-induced foci. Thus, the repressive factors are required for BRCA1 function in promoting the repositioning of 53BP1 during HR. Additionally, depletion of these repressive factors in undamaged cells causes diminished sister chromatid association at centromeric sequences. We propose a model for how these findings may be functionally linked.

PMID:
26206670
PMCID:
PMC4652757
DOI:
10.1093/nar/gkv722
[Indexed for MEDLINE]
Free PMC Article

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