53BP1 and the LINC Complex Promote Microtubule-Dependent DSB Mobility and DNA Repair.
53BP1 and the LINC Complex Promote Microtubule-Dependent DSB Mobility and DNA Repair.
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DOI：
10.1016/j.cell.2015.09.057
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发表时间：
2015-11-05
期刊：
影响因子：
64.5
通讯作者：
de Lange T
中科院分区：
文献类型：
--
作者：
Lottersberger F;Karssemeijer RA;Dimitrova N;de Lange T
在酵母和哺乳动物细胞中已经注意到双链断裂（DSB）周围的染色质的移动性增加，但是它是如何驱动的以及它是否有助于DSB修复仍然不清楚。在这里，我们使用基于端粒的系统来跟踪活细胞中高分辨率的DNA损伤灶。我们发现，受损染色质的更大的流动性需要53 BP 1，SUN 1/2在核骨架和细胞骨架（LINC）复合物和动态微管的连接。数据进一步表明，偏移促进功能失调的端粒的非同源末端连接，并涉及端粒融合中的Nesprin-4和驱动蛋白。53 BP 1/LINC/微管依赖性迁移率在辐射诱导的DSB中也是明显的，并且有助于BRCA 1缺陷细胞中药物诱导的DSB的错误重新连接，这表明DSB迁移率在具有许多DSB的细胞中可能是有害的。相反，在细胞只有一个或几个病变的生理条件下，DSB迁移率被提出来防止DNA修复中的错误。
Increased mobility of chromatin surrounding Double Strand Breaks (DSBs) has been noted in yeast and mammalian cells but how it is driven and whether it contributes to DSB repair remain unclear. Here, we use a telomere-based system to track DNA damage foci with high resolution in living cells. We find that the greater mobility of damaged chromatin requires 53BP1, SUN1/2 in the Linker of the Nucleoskeleton and Cytoskeleton (LINC) complex and dynamic microtubules. The data further demonstrate that the excursions promote non-homologous end joining of dysfunctional telomeres and implicated Nesprin-4 and kinesins in telomere fusion. 53BP1/LINC/microtubule-dependent mobility is also evident at irradiation-induced DSBs and contributes to the mis-rejoining of drug-induced DSBs in BRCA1-deficient cells showing that DSB mobility can be detrimental in cells with numerous DSBs. In contrast, under physiological conditions where cells have only one or a few lesions, DSB mobility is proposed to prevent errors in DNA repair.