Ataxin-3 promotes genome integrity by stabilizing Chk1.
Ataxin-3 promotes genome integrity by stabilizing Chk1.
复制标题
Ataxin-3 通过稳定 Chk1 来促进基因组完整性。
DOI：
10.1093/nar/gkx095
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发表时间：
2017-05-05
影响因子：
14.9
通讯作者：
Tang TS
中科院分区：
文献类型：
--
作者：
Tu Y;Liu H;Zhu X;Shen H;Ma X;Wang F;Huang M;Gong J;Li X;Wang Y;Guo C;Tang TS
Chk1蛋白对真核细胞的基因组完整性维持和细胞存活至关重要。在长时间的复制应激后，Chk1可以靶向蛋白酶体降解，在DNA修复完成后终止检查点信号传导。为了确保DNA损伤检查点和DNA修复信号的正常激活，生理条件下需要保持Chk1的稳态水平。在这里，我们报道了一个紧密调节Chk1稳定性的动态信号通路。在不受干扰的条件下和DNA损伤时，ataxin-3 （ATX3）与Chk1相互作用，保护Chk1免受DDB1/CUL4A-和FBXO6/ cul1介导的多泛素化和随后的降解，从而促进DNA修复和检查点信号传导。在长时间的复制胁迫下，ATX3与Chk1分离，同时Chk1与其E3连接酶之间的结合更强，导致Chk1蛋白酶体降解。ATX3缺乏导致Chk1丰度明显降低，DNA损伤反应降低，G2/M检查点缺陷，复制应激后细胞存活率降低，这些都可以通过ATX3的异位表达来挽救。综上所述，这些发现表明ATX3是Chk1的一种新的去泛素酶，为Chk1在基因组完整性维持中的稳定提供了新的机制。
Abstract The Chk1 protein is essential for genome integrity maintenance and cell survival in eukaryotic cells. After prolonged replication stress, Chk1 can be targeted for proteasomal degradation to terminate checkpoint signaling after DNA repair finishes. To ensure proper activation of DNA damage checkpoint and DNA repair signaling, a steady-state level of Chk1 needs to be retained under physiological conditions. Here, we report a dynamic signaling pathway that tightly regulates Chk1 stability. Under unperturbed conditions and upon DNA damage, ataxin-3 (ATX3) interacts with Chk1 and protects it from DDB1/CUL4A- and FBXO6/CUL1-mediated polyubiquitination and subsequent degradation, thereby promoting DNA repair and checkpoint signaling. Under prolonged replication stress, ATX3 dissociates from Chk1, concomitant with a stronger binding between Chk1 and its E3 ligase, which causes Chk1 proteasomal degradation. ATX3 deficiency results in pronounced reduction of Chk1 abundance, compromised DNA damage response, G2/M checkpoint defect and decreased cell survival after replication stress, which can all be rescued by ectopic expression of ATX3. Taken together, these findings reveal ATX3 to be a novel deubiquitinase of Chk1, providing a new mechanism of Chk1 stabilization in genome integrity maintenance.