title: The nuclear oncogene SET controls DNA repair by KAP1 and HP1 retention to chromatin.
abstract: Cells experience damage from exogenous and endogenous sources that endanger genome stability. Several cellular pathways have evolved to detect DNA damage and mediate its repair. Although many proteins have been implicated in these processes, only recent studies have revealed how they operate in the context of high-ordered chromatin structure. Here, we identify the nuclear oncogene SET (I2PP2A) as a modulator of DNA damage response (DDR) and repair in chromatin surrounding double-strand breaks (DSBs). We demonstrate that depletion of SET increases DDR and survival in the presence of radiomimetic drugs, while overexpression of SET impairs DDR and homologous recombination (HR)-mediated DNA repair. SET interacts with the Kruppel-associated box (KRAB)-associated co-repressor KAP1, and its overexpression results in the sustained retention of KAP1 and Heterochromatin protein 1 (HP1) on chromatin. Our results are consistent with a model in which SET-mediated chromatin compaction triggers an inhibition of DNA end resection and HR.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104 Centre National de la Recherche Scientifique (CNRS), UdS, INSERM U964, BP 10142, 67404 Illkirch Cedex, Strasbourg, France.
authors.forename: Alkmini
authors.initials: A
authors.lastname: Kalousi
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104 Centre National de la Recherche Scientifique (CNRS), UdS, INSERM U964, BP 10142, 67404 Illkirch Cedex, Strasbourg, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Hoffbeck
authors.affiliation: Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 11527 Athens, Greece.
authors.forename: Platonas N
authors.initials: PN
authors.lastname: Selemenakis
authors.affiliation: Departments of Pathology and Biochemistry & Molecular Biology, Dalhousie University, B3H 4R2 Halifax, NS, Canada; Beatrice Hunter Cancer Research Institute, B3H 4R2 Halifax, NS, Canada.
authors.forename: Jordan
authors.initials: J
authors.lastname: Pinder
authors.affiliation: QIMR Berghofer Medical Research Institute, QLD 4006 Herston, Australia.
authors.forename: Kienan I
authors.initials: KI
authors.lastname: Savage
authors.affiliation: QIMR Berghofer Medical Research Institute, QLD 4006 Herston, Australia.
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104 Centre National de la Recherche Scientifique (CNRS), UdS, INSERM U964, BP 10142, 67404 Illkirch Cedex, Strasbourg, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Brino
authors.affiliation: Departments of Pathology and Biochemistry & Molecular Biology, Dalhousie University, B3H 4R2 Halifax, NS, Canada; Beatrice Hunter Cancer Research Institute, B3H 4R2 Halifax, NS, Canada.
authors.forename: Graham
authors.initials: G
authors.lastname: Dellaire
authors.affiliation: Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 11527 Athens, Greece; Faculty Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, M13 9PL Manchester, UK; Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece.
authors.forename: Vassilis G
authors.initials: VG
authors.lastname: Gorgoulis
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104 Centre National de la Recherche Scientifique (CNRS), UdS, INSERM U964, BP 10142, 67404 Illkirch Cedex, Strasbourg, France. Electronic address: evisou@igbmc.fr.
authors.forename: Evi
authors.initials: E
authors.lastname: Soutoglou
mesh_terms: D002843:Chromatin / Q000235:genetics*; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000096:biosynthesis / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D006570:Heterochromatin / Q000235:genetics; D056488:Histone Chaperones / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D059767:Recombinational DNA Repair / Q000235:genetics*; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006570:Heterochromatin; D056488:Histone Chaperones; D012097:Repressor Proteins; C513473:SET protein, human; D014157:Transcription Factors; D000090266:Chromobox Protein Homolog 5; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28