The Mre11-Rad50-Nbs1 complex mediates the robust recruitment of Polo to DNA lesions during mitosis in Drosophila
The Mre11-Rad50-Nbs1 complex mediates the robust recruitment of Polo to DNA lesions during mitosis in Drosophila
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DOI：
10.1242/jcs.244442
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发表时间：
2020-07-01
影响因子：
4
通讯作者：
Royou, Anne
中科院分区：
文献类型：
--
作者：
Landmann, Cedric;Pierre-Elies, Priscillia;Royou, Anne
DNA损伤传感器Mre 11-Rad 50-Nbs 1复合物和波罗激酶在有丝分裂期间被募集到DNA损伤。然而，他们的招募机制是难以捉摸的。在这里，使用活细胞成像结合显微照射的单染色体，我们分析了动态的波罗和Mre 11在果蝇有丝分裂过程中的DNA损伤。这两种蛋白质表现出不同的动力学。而波罗动力学在双链断裂（DSB）是Cdk 1驱动的，Mre 11迅速，但短暂地与DSB的有丝分裂相无关，并重新与DSB在进行间期。从机制上讲，波罗激酶活性是其自身募集以及有丝分裂蛋白BubR 1和Bub 3募集到DSB所必需的。此外，在有丝分裂DSB中，Rad 50的缺失严重损害了波罗动力学。相反，Mre 11与染色质的异位拴系足以招募波罗。我们的研究强调了一种新的途径，该途径将DSB传感器Mre 11-Rad 50-Nbs 1复合物和波罗激酶联系起来，以启动对有丝分裂过程中DNA损伤的迅速、决定性反应。
The DNA damage sensor Mre11-Rad50-Nbs1 complex and Polo kinase are recruited to DNA lesions during mitosis. However, their mechanism of recruitment is elusive. Here, using live-cell imaging combined with micro-irradiation of single chromosomes, we analyze the dynamics of Polo and Mre11 at DNA lesions during mitosis in Drosophila. These two proteins display distinct kinetics. Whereas Polo kinetics at double-strand breaks (DSBs) are Cdk1-driven, Mre11 promptly but briefly associates with DSBs regardless of the phase of mitosis and re-associates with DSBs in the proceeding interphase. Mechanistically, Polo kinase activity is required for its own recruitment and that of the mitotic proteins BubR1 and Bub3 to DSBs. Moreover, depletion of Rad50 severely impaired Polo kinetics at mitotic DSBs. Conversely, ectopic tethering of Mre11 to chromatin was sufficient to recruit Polo. Our study highlights a novel pathway that links the DSB sensor Mre11-Rad50-Nbs1 complex and Polo kinase to initiate a prompt, decisive response to the presence of DNA damage during mitosis.