The Nuclear Oncogene SET Controls DNA Repair by KAP1 and HP1 Retention to Chromatin
Alkmini Kalousi,
Anne-Sophie Hoffbeck,
Platonas N. Selemenakis,
Jordan Pinder,
Kienan I. Savage,
Kum Kum Khanna,
Laurent Brino,
Graham Dellaire,
Vassilis G. Gorgoulis,
Evi Soutoglou
Affiliations
Alkmini Kalousi
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
Anne-Sophie Hoffbeck
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
Platonas N. Selemenakis
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 11527 Athens, Greece
Jordan Pinder
Departments of Pathology and Biochemistry & Molecular Biology, Dalhousie University, B3H 4R2 Halifax, NS, Canada
Kienan I. Savage
QIMR Berghofer Medical Research Institute, QLD 4006 Herston, Australia
Kum Kum Khanna
QIMR Berghofer Medical Research Institute, QLD 4006 Herston, Australia
Laurent Brino
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
Graham Dellaire
Departments of Pathology and Biochemistry & Molecular Biology, Dalhousie University, B3H 4R2 Halifax, NS, Canada
Vassilis G. Gorgoulis
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 11527 Athens, Greece
Evi Soutoglou
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
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.
