Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Nature. 2013 Jun 13;498(7453):246-50. doi: 10.1038/nature12147. Epub 2013 Jun 2.
DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage.
DNA 损伤激活了一个信号网络，该网络阻止细胞周期进程，招募 DNA 修复因子和/或触发衰老或程序性细胞死亡。染色质结构的改变与 DNA 损伤反应的起始和传播有关。在这里，我们通过监测电离辐射诱导的信号和反应事件，进一步研究了染色质结构在 DNA 损伤反应中的作用，该事件使用了一个高内涵多重 RNA 介导的干扰染色质修饰和相互作用基因的筛选。我们发现 Brd4 的一种异构体，一种溴结构域和额外末端（BET）家族成员，通过溴结构域相互作用将凝聚素 II 染色质重塑复合物招募到乙酰化组蛋白上，从而作为 DNA 损伤反应信号的内源性抑制剂发挥作用。这种异构体的缺失导致染色质结构松弛、细胞周期检查点快速恢复和照射后存活率提高，而该异构体的功能获得则使染色质结构紧凑、DNA 损伤反应信号减弱和辐射诱导的致死性增强。这些数据表明，先前因其在转录控制中的作用而闻名的 Brd4 作为一种可以调节 DNA 损伤信号反应的染色质绝缘子。
