The bromodomain protein Brd4 insulates chromatin from DNA damage signalling.
The bromodomain protein Brd4 insulates chromatin from DNA damage signalling.
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DNA损伤激活信号网络，阻断细胞周期进程，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损伤反应的启动和传播有关。在这里，我们进一步调查的作用，染色质结构的DNA损伤反应，通过监测电离辐射诱导的信号和响应事件与高含量的多重RNA介导的干扰屏幕染色质修饰和相互作用的基因。我们发现Brd 4的同种型，溴结构域和额外的终端（BET）的家庭成员，作为一个内源性抑制剂的DNA损伤反应信号通过招募缩合蛋白II染色质重塑复合物乙酰化组蛋白通过溴结构域的相互作用。这种异构体的损失导致松弛的染色质结构，快速细胞周期检查点恢复和增强的辐射后的存活，而这种异构体的功能性增益压缩染色质，减弱DNA损伤反应信号传导和增强辐射诱导的致死性。这些数据暗示Brd 4，以前已知其在转录控制中的作用，作为染色质的绝缘体，可以调节对DNA损伤的信号转导反应。
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.