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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743
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Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743

机译：复制和同源重组修复通过抗肿瘤烷化剂ecteinascidin 743调节DNA双链断裂的形成

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摘要

Adducts induced by the antitumor alkylator ecteinascidin 743 (ET-743, Yondelis, trabectedin) represent a unique challenge to the DNA repair machinery because no pathway examined to date is able to remove the ET adducts, whereas cells deficient in nucleotide excision repair show increased resistance. We here describe the processing of the initial ET adducts into cytotoxic lesions and characterize the influence of cellular repair pathways on this process. Our findings show that exposure of proliferating mammalian cells to pharmacologically relevant concentrations of ET-743 is accompanied by rapid formation of DNA double-strand breaks (DSBs), as shown by the neutral comet assay and induction of focalized phosphorylated H2AX. The ET adducts are stable and can be converted into DSBs hours after the drug has been removed. Loss of homologous recombination repair has no influence on the initial levels of DSBs but is associated with the persistence of unrepaired DSBs after ET-743 is removed, resulting in extensive chromosomal abnormalities and pronounced sensitivity to the drug. In comparison, loss of nonhomologous end-joining had only modest effect on the sensitivity. The identification of DSB. formation as a key step in the processing of ET-743 lesions represents a novel mechanism of action for the drug that is in agreement with its unusual potency. Because loss of repair proteins is common in human tumors, expression levels of selected repair factors may be useful in identifying patients particularly likely to benefit, or not, from treatment with ET-743.
机译：抗肿瘤烷基化ecteinascidin 743（ET-743，Yondelis，trabectedin）诱导的加合物对DNA修复机制提出了独特的挑战，因为迄今尚未检测到任何途径都能去除ET加合物，而缺乏核苷酸切除修复功能的细胞显示出增加的耐药性。我们在这里描述了最初的ET加合物加工成细胞毒性损伤的过程，并表征了细胞修复途径对该过程的影响。我们的发现表明，如中性彗星试验和聚焦磷酸化H2AX的诱导所显示，增殖的哺乳动物细胞暴露于药理学相关浓度的ET-743伴随着DNA双链断裂（DSB）的快速形成。 ET加合物是稳定的，可以在去除药物后数小时将其转化为DSB。同源重组修复的丧失对DSBs的初始水平没有影响，但是与ET-743去除后未修复的DSBs的持续存在有关，导致广泛的染色体异常和对药物的显着敏感性。相比之下，非同源末端连接的丧失仅对敏感性有中等程度的影响。 DSB的标识。形成作为ET-743病变处理中的关键步骤代表了该药物的新作用机理，这与其非同寻常的功效相符。由于修复蛋白的丢失在人类肿瘤中很常见，因此选择的修复因子的表达水平可能有助于确定特别可能从ET-743治疗中受益或未受益的患者。

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