A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses.
A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses.
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DOI：
10.1038/nchembio.1455
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发表时间：
2014-04
影响因子：
14.8
通讯作者：
Zhuang, Zhihao
中科院分区：
文献类型：
--
作者：
Liang, Qin;Dexheimer, Thomas S.;Zhang, Ping;Rosenthal, Andrew S.;Villamil, Mark A.;You, Changjun;Zhang, Qiuting;Chen, Junjun;Ott, Christine A.;Sun, Hongmao;Luci, Diane K.;Yuan, Bifeng;Simeonov, Anton;Jadhav, Ajit;Xiao, Hui;Wang, Yinsheng;Maloney, David J.;Zhuang, Zhihao
蛋白质泛素化和去泛素化是真核生物中控制大量细胞通路和信号网络的核心。虽然泛素化在真核生物DNA损伤反应中的重要作用已经被确定，但去泛素化过程仍然不清楚。去泛素化酶（DUBs）活性的干扰化学探针是表征去泛素化的细胞功能所必需的。在这里，我们报告了ML 323（2），一种USP 1-UAF 1去泛素化酶复合物的高效抑制剂，对人DUB、去SUMO化酶、去泛素化酶和无关蛋白酶具有优异的选择性。使用ML 323，我们询问去泛素化的细胞响应紫外线和顺铂诱导的DNA损伤，并揭示了新的见解去泛素化的DNA translesion合成和范可尼贫血途径的要求。此外，ML 323增强顺铂在非小细胞肺癌和骨肉瘤细胞中的细胞毒性。我们的研究结果指出USP 1-UAF 1是DNA损伤反应的关键调节因子，也是克服对铂类抗癌药物耐药性的靶点。
Protein ubiquitination and deubiquitination are central to the control of a large number of cellular pathways and signaling networks in eukaryotes. Although the essential roles of ubiquitination have been established in the eukaryotic DNA damage response, the deubiquitination process remains poorly defined. Chemical probes that perturb the activity of deubiquitinases (DUBs) are needed to characterize the cellular function of deubiquitination. Here we report ML323 (2), a highly potent inhibitor of the USP1-UAF1 deubiquitinase complex with excellent selectivity against human DUBs, deSUMOylase, deneddylase and unrelated proteases. Using ML323, we interrogated deubiquitination in the cellular response to UV- and cisplatin-induced DNA damage and revealed new insights into the requirement of deubiquitination in the DNA translesion synthesis and Fanconi anemia pathways. Moreover, ML323 potentiates cisplatin cytotoxicity in non-small cell lung cancer and osteosarcoma cells. Our findings point to USP1-UAF1 as a key regulator of the DNA damage response and a target for overcoming resistance to the platinum-based anticancer drugs.
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影响因子：
4.8
作者：
Baker, David J.;Wuenschell, Gerald;O'Connor, Timothy R.
通讯作者：
O'Connor, Timothy R.
影响因子：
3.5
作者：
Guervilly JH;Renaud E;Takata M;Rosselli F
通讯作者：
Rosselli F
DOI：
10.1073/pnas.0403489101
发表时间：
2004-09-28
影响因子：
11.1
作者：
Delaney, JC;Essigmann, JM
通讯作者：
Essigmann, JM
影响因子：
2.9
作者：
Khrapunovich-Baine, Marina;Menon, Vilas;Verdier-Pinard, Pascal;Smith, Amos B., III;Angeletti, Ruth Hogue;Fiser, Andras;Horwitz, Susan Band;Xiao, Hui
通讯作者：
Xiao, Hui
影响因子：
11.2
作者：
Albertella, MR;Green, CM;O'Connor, MJ
通讯作者：
O'Connor, MJ