RNF8-and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites
RNF8-and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites
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DOI：
10.1038/emboj.2012.47
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发表时间：
2012-04-18
期刊：
影响因子：
11.4
通讯作者：
Richard, Stephane
中科院分区：
文献类型：
--
作者：
Mallette, Frederick A.;Mattiroli, Francesca;Richard, Stephane
作为对DNA损伤的反应，细胞启动复杂的信号级联反应，导致生长停滞和DNA修复。53BP1募集到受损部位需要激活E3泛素连接酶RNF8和RNF168控制的泛素化级联反应，以及赖氨酸20上组蛋白H4的甲基化。然而，调控甲基化组蛋白的可及性，使53BP1募集到DNA断裂的分子事件尚不清楚。在这里，我们发现像53BP1一样，JMJD2A（也称为KDM4A）串联都铎结构域结合二甲基化组蛋白H4K20；然而，JMJD2A在DNA损伤后以依赖rnf8的方式被蛋白酶体降解。我们证明了JMJD2A被RNF8和RNF168泛素化。此外，JMJD2A的异位表达消除了53BP1在DNA损伤位点的募集，表明其在甲基化组蛋白标记中拮抗53BP1的作用。联合敲除JMJD2A和JMJD2B显著挽救了RNF8-和rnf168缺陷细胞形成53BP1灶的能力。我们提出，rnf8依赖性的JMJD2A降解通过控制53BP1在DNA损伤位点的募集来调节DNA修复。EMBO杂志（2012）31,1865-1878。doi: 10.1038 / emboj.2012.47;主题类别：蛋白质；基因组稳定性与动力学
In response to DNA damage, cells initiate complex signalling cascades leading to growth arrest and DNA repair. The recruitment of 53BP1 to damaged sites requires the activation of the ubiquitination cascade controlled by the E3 ubiquitin ligases RNF8 and RNF168, and methylation of histone H4 on lysine 20. However, molecular events that regulate the accessibility of methylated histones, to allow the recruitment of 53BP1 to DNA breaks, are unclear. Here, we show that like 53BP1, the JMJD2A (also known as KDM4A) tandem tudor domain binds dimethylated histone H4K20; however, JMJD2A is degraded by the proteasome following the DNA damage in an RNF8-dependent manner. We demonstrate that JMJD2A is ubiquitinated by RNF8 and RNF168. Moreover, ectopic expression of JMJD2A abrogates 53BP1 recruitment to DNA damage sites, indicating a role in antagonizing 53BP1 for methylated histone marks. The combined knockdown of JMJD2A and JMJD2B significantly rescued the ability of RNF8- and RNF168-deficient cells to form 53BP1 foci. We propose that the RNF8-dependent degradation of JMJD2A regulates DNA repair by controlling the recruitment of 53BP1 at DNA damage sites. The EMBO Journal (2012) 31, 1865-1878. doi:10.1038/emboj.2012.47; Published online 28 February 2012 Subject Categories: proteins; genome stability & dynamics