Localisation of Nup153 and SENP1 to nuclear pore complexes is required for 53BP1-mediated DNA double-strand break repair
Localisation of Nup153 and SENP1 to nuclear pore complexes is required for 53BP1-mediated DNA double-strand break repair
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DOI：
10.1242/jcs.198390
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发表时间：
2017-07-15
影响因子：
4
通讯作者：
Fahrenkrog, Birthe
中科院分区：
文献类型：
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作者：
Duheron, Vincent;Nilles, Nadine;Fahrenkrog, Birthe
核孔复合物（NPCs）的核篮由Nup153、Nup50和Tpr三种核孔蛋白组成。Nup153通过促进53BP1（也称为TP53BP1）的核输入，在DNA双链断裂（DSB）修复中发挥作用，53BP1是DNA损伤反应的中介。在这里，我们提供的证据表明，Nup153的缺失损害了53BP1的sumoylation，这是53BP1在dsb中有效积累的先决条件。Nup153的缺失导致53BP1的SUMO1修饰减少，npc的SUMO蛋白酶SENP1位移。在Nup153缺失的情况下，SENP1与npc的人工连接恢复了非同源末端连接（NHEJ），并重新建立了53BP1的sumoylation。此外，Nup50和Tpr，另外两个核篮核孔蛋白，也以不同于Nup153的方式促进DSB的适当修复。与Nup153的作用类似，Tpr与NHEJ和同源重组（HR）有关，而Nup50的缺失仅影响NHEJ。尽管准确的NHEJ需要所有三种核孔蛋白，但53BP1的核输入和53BP1的senp1依赖性sumomylation只需要Nup153。我们的数据支持Nup153作为53BP1活性和高效NHEJ的重要调节因子的作用。
The nuclear basket of nuclear pore complexes (NPCs) is composed of three nucleoporins: Nup153, Nup50 and Tpr. Nup153 has a role in DNA double-strand break (DSB) repair by promoting nuclear import of 53BP1 (also known as TP53BP1), a mediator of the DNA damage response. Here, we provide evidence that loss of Nup153 compromises 53BP1 sumoylation, a prerequisite for efficient accumulation of 53BP1 at DSBs. Depletion of Nup153 resulted in reduced SUMO1 modification of 53BP1 and the displacement of the SUMO protease SENP1 from NPCs. Artificial tethering of SENP1 to NPCs restored non-homologous end joining (NHEJ) in the absence of Nup153 and re-established 53BP1 sumoylation. Furthermore, Nup50 and Tpr, the two other nuclear basket nucleoporins, also contribute to proper DSB repair, in a manner distinct from Nup153. Similar to the role of Nup153, Tpr is implicated in NHEJ and homologous recombination (HR), whereas loss of Nup50 only affects NHEJ. Despite the requirement of all three nucleoporins for accurate NHEJ, only Nup153 is needed for proper nuclear import of 53BP1 and SENP1-dependent sumoylation of 53BP1. Our data support the role of Nup153 as an important regulator of 53BP1 activity and efficient NHEJ.