WRN counteracts the NHEJ pathway upon camptothecin exposure
WRN counteracts the NHEJ pathway upon camptothecin exposure
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DOI：
10.1016/j.bbrc.2007.01.175
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发表时间：
2007-04-06
影响因子：
3.1
通讯作者：
Enomoto, Takemi
中科院分区：
文献类型：
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作者：
Otsuki, Makoto;Seki, Masayuki;Enomoto, Takemi
我们通过建立KU70(-/-)/WRN-/-和DNA-PKCs-‘-1-1WRN-/-双基因敲除鸡DT40细胞，研究了Werner综合征基因产物WRN与Ku70以及WRN与DNA-PKcs之间的相互作用。当用DNA拓扑异构酶I的抑制剂喜树碱(CPT)处理时，WRN-/-细胞表现出比野生型细胞更高的敏感性，而KU70(-/-)和DNA-PKcs(-/-/-)细胞则表现出超抗性。KU70或DNA-PKcs的破坏抑制了WRN-/-细胞对CPT的敏感性，使它们与KU70(-/-)和DNA-PKcs(-/-/-)细胞一样对CPT具有抵抗力。另一方面，与WRN类似的RecQ解旋酶缺陷的BLM-/-细胞的CPT敏感性因KU70的缺失而增强。将讨论WRN在涉及Ku70和DNA-PKcs的DNA修复的非同源末端连接途径中的作用，这可能是CPT存在时致死的原因。(C)2007 Elsevier Inc.保留所有权利。
We investigated the function of the interaction between WRN (Werner syndrome gene product) and Ku70 and between WRN and DNA-PKcs, which are components of the DNA-PKcs/Ku70/Ku80 complex, by generating KU70(-/-)/WRN-/- and DNA-PKCs-'-1-1 WRN-/- double-gene knockout chicken DT40 cells. When treated with camptothecin (CPT), an inhibitor of DNA topoisomerase I, WRN-/- cells showed higher sensitivity than wild-type cells, whereas KU70(-/-) and DNA-PKcs(-/-/-) cells showed hyper-resistance. Disruption of KU70 or DNA-PKcs suppressed the sensitivity of WRN-/- cells to CPT, rendering them as resistant to CPT treatment as KU70(-/-) and DNA-PKcs(-/-/-) cells. On the other hand, CPT sensitivity of BLM-/- cells, which are defective in a RecQ helicase similar to WRN, was enhanced by deletion of KU70. The implications for the function of WRN in the non-homologous end-joining pathway of DNA repair involving Ku70 and DNA-PKcs, which may be the cause of lethality in the presence of CPT, will be discussed. (c) 2007 Elsevier Inc. All rights reserved.