Histone demethylase KDM5B is a key regulator of genome stability
Histone demethylase KDM5B is a key regulator of genome stability
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组蛋白去甲基化酶 KDM5B 是基因组稳定性的关键调节因子
DOI：
10.1073/pnas.1324036111
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发表时间：
2014-05-13
影响因子：
11.1
通讯作者：
Shi, Lei
中科院分区：
文献类型：
--
作者：
Li, Xin;Liu, Ling;Shi, Lei
DNA双链断裂通常在高度组织化的染色质中修复。然而，表观遗传机制如何参与维持遗传保真度仍然知之甚少。在这里，我们报告赖氨酸特异性组蛋白去甲基化酶5 B（KDM 5 B），一个定义明确的转录抑制因子，促进双链断裂信号，并需要有效的DNA修复。我们证明了KDM 5 B在DNA损伤后协调检查点激活和细胞存活的功能。我们的研究结果提供的证据表明，KDM 5 B是一个重要的基因组看护和基因组稳定性的关键调节因子。基因组稳定性的维持对于正常的生物体发育至关重要，对于预防癌症等疾病至关重要。随着遗传信息被包装到染色质中，越来越清楚的是染色质环境在DNA损伤反应中起着重要作用。然而，DNA修复是如何由表观遗传机制控制的还没有完全弄清楚。在这里，我们报告的赖氨酸特异性组蛋白去甲基化酶5 B（KDM 5 B），一个成员的JmjC结构域的组蛋白去甲基化酶，作为一个重要的球员在多个方面的DNA双链断裂（DSB）在人类细胞中的反应的鉴定和表征。我们发现，KDM 5 B成为丰富的DNA损伤位点后，铁辐射和核酸内切酶处理的聚（ADP核糖）聚合酶1-和组蛋白变体macroH2A1.1依赖的方式。我们发现，KDM 5 B是必需的有效的DSB修复和招聘Ku 70和BRCA 1，非同源末端连接和同源重组的必要组成部分，分别。值得注意的是，KDM 5 B缺陷会使DNA修复过程脱离，促进自发性DNA损伤，激活p53信号传导，并使细胞对遗传毒性损伤敏感。我们的研究结果表明，KDM 5 B是一个真正的DNA损伤反应蛋白，并表明KDM 5 B是一个重要的基因组看护和基因组稳定性的关键调节剂，增加了对表观遗传学在维持遗传保真度的作用的理解。
Significance DNA double-strand breaks are generally repaired in the context of highly organized chromatin. However, how epigenetic mechanisms are involved in the maintenance of the genetic fidelity remains poorly understood. Here we report that lysine-specific histone demethylase 5B (KDM5B), a well-defined transcriptional repressor, promotes double-strand break signaling and is required for efficient DNA repairs. We demonstrated that KDM5B, in doing so, functions to orchestrate checkpoint activation and cell survival after DNA damage. Our results provide evidence to indicate that KDM5B is an important genome caretaker and a critical regulator of genome stability. Maintenance of genomic stability is essential for normal organismal development and is vital to prevent diseases such as cancer. As genetic information is packaged into chromatin, it has become increasingly clear that the chromatin environment plays an important role in DNA damage response. However, how DNA repair is controlled by epigenetic mechanisms is not fully understood. Here we report the identification and characterization of lysine-specific histone demethylase 5B (KDM5B), a member of the JmjC domain-containing histone demethylases, as an important player in multiple aspects of DNA double-strand break (DSB) response in human cells. We found that KDM5B becomes enriched in DNA-damage sites after ironizing radiation and endonuclease treatment in a poly(ADP ribose) polymerase 1- and histone variant macroH2A1.1-dependent manner. We showed that KDM5B is required for efficient DSB repair and for the recruitment of Ku70 and BRCA1, the essential component of nonhomologous end-joining and homologous recombination, respectively. Significantly, KDM5B deficiency disengages the DNA repair process, promotes spontaneous DNA damage, activates p53 signaling, and sensitizes cells to genotoxic insults. Our results suggest that KDM5B is a bona fide DNA damage response protein and indicate that KDM5B is an important genome caretaker and a critical regulator of genome stability, adding to the understanding of the roles of epigenetics in the maintenance of genetic fidelity.