DNA damage-induced activation of CUL4B targets HUWE1 for proteasomal degradation.
DNA damage-induced activation of CUL4B targets HUWE1 for proteasomal degradation.
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DNA 损伤诱导 CUL4B 激活 HUWE1 进行蛋白酶体降解
DOI：
10.1093/nar/gkv325
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发表时间：
2015-05-19
影响因子：
14.9
通讯作者：
Shao G
中科院分区：
文献类型：
--
作者：
Yi J;Lu G;Li L;Wang X;Cao L;Lin M;Zhang S;Shao G
E3泛素连接酶HUWE1/Mule/ARF-BP1在整合/协调DNA损伤修复和细胞凋亡等多种细胞过程中发挥重要作用。先前的研究表明，通过靶向MCL-1降解蛋白酶体，HUWE1在DNA损伤诱导的细胞凋亡的早期阶段是必需的。然而，HUWE1随后失活，促进细胞存活和随后的DNA损伤修复过程。在这一过程中，其调控机制在很大程度上仍未明确。在这里，我们发现Cullin4B-RING E3连接酶（CRL4B）是HUWE1响应DNA损伤的蛋白酶体降解所必需的。CUL4B以依赖nedd8的方式激活，在体外和体内都泛素化HUWE1。CUL4B的缺失稳定了HUWE1，从而加速了MCL-1的降解，导致细胞凋亡的诱导增加。因此，缺乏CUL4B的细胞对DNA损伤试剂的敏感性增加。更重要的是，在CUL4B缺失后，这些表型可以通过同时缺失HUWE1而得到拯救，这与CUL4B调节HUWE1的作用是一致的。总的来说，这些结果确定了CRL4B是针对HUWE1的蛋白酶体降解以响应DNA损伤的重要E3连接酶，并提供了针对HUWE1和CUL4B E3连接酶的潜在癌症治疗策略。
The E3 ubiquitin ligase HUWE1/Mule/ARF-BP1 plays an important role in integrating/coordinating diverse cellular processes such as DNA damage repair and apoptosis. A previous study has shown that HUWE1 is required for the early step of DNA damage-induced apoptosis, by targeting MCL-1 for proteasomal degradation. However, HUWE1 is subsequently inactivated, promoting cell survival and the subsequent DNA damage repair process. The mechanism underlying its regulation during this process remains largely undefined. Here, we show that the Cullin4B-RING E3 ligase (CRL4B) is required for proteasomal degradation of HUWE1 in response to DNA damage. CUL4B is activated in a NEDD8-dependent manner, and ubiquitinates HUWE1 in vitro and in vivo. The depletion of CUL4B stabilizes HUWE1, which in turn accelerates the degradation of MCL-1, leading to increased induction of apoptosis. Accordingly, cells deficient in CUL4B showed increased sensitivity to DNA damage reagents. More importantly, upon CUL4B depletion, these phenotypes can be rescued through simultaneous depletion of HUWE1, consistent with the role of CUL4B in regulating HUWE1. Collectively, these results identify CRL4B as an essential E3 ligase in targeting the proteasomal degradation of HUWE1 in response to DNA damage, and provide a potential strategy for cancer therapy by targeting HUWE1 and the CUL4B E3 ligase.
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影响因子：
16
作者：
Kurz, Thimo;Chou, Yang-Chieh;Sicheri, Frank
通讯作者：
Sicheri, Frank
影响因子：
16
作者：
Ciccia A;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
4.3
作者：
Higa, LA;Yang, XM;Zhang, H
通讯作者：
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X 连锁智力障碍基因 CUL4B 以 Jab1/CSN5 为目标进行降解并调节骨形态发生蛋白信号传导。
DOI：
10.1016/j.bbadis.2013.01.015
发表时间：
2013-05-01
影响因子：
6.2
作者：
He, Fengjuan;Lu, Defen;Gong, Yaoqin
通讯作者：
Gong, Yaoqin
影响因子：
3.8
作者：
Al-Hakim A;Escribano-Diaz C;Landry MC;O'Donnell L;Panier S;Szilard RK;Durocher D
通讯作者：
Durocher D