Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair
Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair
复制标题
DOI：
10.1038/91008
复制
发表时间：
2001-08-01
期刊：
影响因子：
82.9
通讯作者：
Pommier, Y
中科院分区：
文献类型：
--
作者：
Takebayashi, Y;Pourquier, P;Pommier, Y
在研究从加勒比海海鞘中分离的天然海产新型抗癌药物ecteinascidin 743 （Et743）的过程中，我们发现了DNA核苷酸切除修复（NER）介导的一种新的细胞杀伤机制。选择抗Et743的癌细胞系在一个区域发生染色体改变，该区域包括与遗传性疾病着色性干皮病（XPG，也称为Ercc5）有关的基因。与野生型XPG互补恢复药物敏感性。缺乏NER基因XPG、XPA、XPD或XPF的着色性干皮细胞对Et743具有抗性，并通过与野生型基因的互补恢复敏感性。此外，对XPC或Cockayne综合征相关基因（CSA和CSS）缺失的细胞的研究表明，药物敏感性特异性依赖于NER的转录偶联途径。我们发现Et743与转录偶联的NER机制相互作用，诱导致命的DNA链断裂。
While investigating the novel anticancer drug ecteinascidin 743 (Et743), a natural marine product isolated from the Caribbean sea squirt, we discovered a new cell-killing mechanism mediated by DNA nucleotide excision repair (NER). A cancer cell line selected for resistance to Et743 had chromosome alterations in a region that included the gene implicated in the hereditary disease xeroderma pigmentosum (XPG, also known as Ercc5). Complementation with wild-type XPG restored the drug sensitivity. Xeroderma pigmentosum cells deficient in the NER genes XPG, XPA, XPD or XPF were resistant to Et743, and sensitivity was restored by complementation with wildtype genes. Moreover, studies of cells deficient in XPC or in the genes implicated in Cockayne syndrome (CSA and CSS) indicated that the drug sensitivity is specifically dependent on the transcription-coupled pathway of NER. We found that Et743 interacts with the transcription-coupled NER machinery to induce lethal DNA strand breaks.