Kalousi Alkmini, Hoffbeck Anne-Sophie, Selemenakis Platonas N, Pinder Jordan, Savage Kienan I, Khanna Kum Kum, Brino Laurent, Dellaire Graham, Gorgoulis Vassilis G, Soutoglou Evi
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.
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 11527 Athens, Greece.
Cell Rep. 2015 Apr 7;11(1):149-63. doi: 10.1016/j.celrep.2015.03.005. Epub 2015 Mar 26.
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.
细胞会受到来自外部和内部的损伤，这些损伤会危及基因组稳定性。细胞进化出了多种途径来检测DNA损伤并介导其修复。尽管许多蛋白质都参与了这些过程，但直到最近的研究才揭示它们在高阶染色质结构背景下是如何运作的。在这里，我们确定核癌基因SET（I2PP2A）是双链断裂（DSB）周围染色质中DNA损伤反应（DDR）和修复的调节剂。我们证明，在存在放射模拟药物的情况下，SET的缺失会增加DDR和细胞存活率，而SET的过表达则会损害DDR和同源重组（HR）介导的DNA修复。SET与Kruppel相关盒（KRAB）相关共抑制因子KAP1相互作用，其过表达导致KAP1和异染色质蛋白1（HP1）在染色质上持续保留。我们的结果与一个模型一致，即SET介导的染色质压缩触发了对DNA末端切除和HR的抑制。
