MRNIP condensates promote DNA double-strand break sensing and end resection.
MRNIP condensates promote DNA double-strand break sensing and end resection.
复制标题
MRNIP 缩合物促进 DNA 双链断裂传感和末端切除
DOI：
10.1038/s41467-022-30303-w
复制
发表时间：
2022-05-12
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
MRE 11/RAD 50/NBS 1（MRN）复合物对DNA双链断裂（DSB）的快速识别对于启动DNA损伤反应和DSB末端切除至关重要。在这里，我们表明，MRN复合物相互作用蛋白（MRNIP）形成液体样的缩合物，以促进同源重组介导的DSB修复。本征无序区是MRNIP凝析油形成的必要条件。在机械上，MRN复合物被区室化并浓缩成核中的MRNIP缩合物。在DSB形成后，MRNIP缩合物迅速移动到受损的DNA，以加速浓缩的MRN复合物与DSB的结合，从而诱导ATM的自磷酸化和随后的DNA损伤反应信号传导的激活。同时，MRNIP冷凝物增强的MRN复合物负载进一步促进DSB末端切除。此外，来自异种移植模型和临床样品的数据证实了MRNIP与辐射抗性之间的相关性。总之，这些结果揭示了MRNIP相分离在DSB反应和MRN复合物介导的DSB末端切除中的重要作用。MRN复合物是DNA双链断裂（DSB）的关键传感器和处理器。在这里，作者表明，MRNIP形成液体状冷凝物，以加速MRN介导的DSB的传感和末端切除，从而促进DSB修复。
The rapid recognition of DNA double-strand breaks (DSBs) by the MRE11/RAD50/NBS1 (MRN) complex is critical for the initiation of DNA damage response and DSB end resection. Here, we show that MRN complex interacting protein (MRNIP) forms liquid-like condensates to promote homologous recombination-mediated DSB repair. The intrinsically disordered region is essential for MRNIP condensate formation. Mechanically, the MRN complex is compartmentalized and concentrated into MRNIP condensates in the nucleus. After DSB formation, MRNIP condensates move to the damaged DNA rapidly to accelerate the binding of DSB by the concentrated MRN complex, therefore inducing the autophosphorylation of ATM and subsequent activation of DNA damage response signaling. Meanwhile, MRNIP condensates-enhanced MRN complex loading further promotes DSB end resection. In addition, data from xenograft models and clinical samples confirm a correlation between MRNIP and radioresistance. Together, these results reveal an important role of MRNIP phase separation in DSB response and the MRN complex-mediated DSB end resection. The MRN complex is a critical sensor and processor of DNA double-strand breaks (DSBs). Here, the authors show that MRNIP forms liquid-like condensates to accelerate the MRN-mediated sensing and end resection of DSB, thereby promoting DSB repair.
登录
查看更多内容
DOI：
10.1073/pnas.1713912115
发表时间：
2018-02-20
影响因子：
11.1
作者：
Chen, Jung-Kuei;Lin, Wen-Ling;Liu, Hung-wen
通讯作者：
Liu, Hung-wen
影响因子：
64.5
作者：
Jachimowicz, Ron D.;Beleggia, Filippo;Shiloh, Yosef
通讯作者：
Shiloh, Yosef
影响因子：
16.8
作者：
通讯作者：
--
影响因子：
3.7
作者：
Ho V;Chung L;Revoltar M;Lim SH;Tut TG;Abubakar A;Henderson CJ;Chua W;Ng W;Lee M;De Souza P;Morgan M;Lee CS;Shin JS
通讯作者：
Shin JS
影响因子：
2.9
作者：
Lee, Hansol D.;Estillore, Armando D.;Tivanski, Alexei V.
通讯作者：
Tivanski, Alexei V.