title: SETDB1, HP1 and SUV39 promote repositioning of 53BP1 to extend resection during homologous recombination in G2 cells.
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.
authors.affiliation: University of Sussex Genome Damage and Stability Centre, East Sussex, BN19RQ, UK.
authors.forename: Meryem
authors.initials: M
authors.lastname: Alagoz
authors.affiliation: University of Sussex Genome Damage and Stability Centre, East Sussex, BN19RQ, UK.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Katsuki
authors.affiliation: Division of Genome Biology, National Cancer Centre Japan Research Institute, Tokyo, 104-0045, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ogiwara
authors.affiliation: Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, 852-8523, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Ogi
authors.affiliation: University of Sussex Genome Damage and Stability Centre, East Sussex, BN19RQ, UK.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shibata
authors.affiliation: 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.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kakarougkas
authors.affiliation: University of Sussex Genome Damage and Stability Centre, East Sussex, BN19RQ, UK p.a.jeggo@sussex.ac.uk.
authors.forename: Penny
authors.initials: P
authors.lastname: Jeggo
mesh_terms: D019313:BRCA1 Protein / Q000378:metabolism; D002478:Cells, Cultured; D002842:Chromatids; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000502:physiology*; D004249:DNA Damage; D059766:DNA End-Joining Repair; D016195:G2 Phase; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D059767:Recombinational DNA Repair; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D019313:BRCA1 Protein; D002868:Chromosomal Proteins, Non-Histone; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D000090266:Chromobox Protein Homolog 5; C407843:SUV39H1 protein, human; D008780:Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human; C515701:SUV39H2 protein, human