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Cell Rep. 2015 Apr 7;11(1):149-63. doi: 10.1016/j.celrep.2015.03.005. Epub 2015 Mar 26.

The nuclear oncogene SET controls DNA repair by KAP1 and HP1 retention to chromatin.

Author information

1
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.
2
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 11527 Athens, Greece.
3
Departments of Pathology and Biochemistry & Molecular Biology, Dalhousie University, B3H 4R2 Halifax, NS, Canada; Beatrice Hunter Cancer Research Institute, B3H 4R2 Halifax, NS, Canada.
4
QIMR Berghofer Medical Research Institute, QLD 4006 Herston, Australia.
5
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.
6
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.

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.

PMID:
25818296
DOI:
10.1016/j.celrep.2015.03.005
[Indexed for MEDLINE]
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