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首页> 外文期刊>Biochemical Pharmacology >Processing of anthracycline-DNA adducts via DNA replication and interstrand crosslink repair pathways
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Processing of anthracycline-DNA adducts via DNA replication and interstrand crosslink repair pathways

机译：通过DNA复制和链间交联修复途径加工蒽环类DNA加合物

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Anthracycline chemotherapeutics are well characterised as poisons of topoisomerase II, however many anthracyclines, including doxorubicin, are also capable of forming drug-DNA adducts. Anthracycline-DNA adducts present an unusual obstacle for cells as they are covalently attached to one DNA strand and stabilised by hydrogen bonding to the other strand. We now show that in cycling cells processing of anthracycline adducts through DNA replication appears dominant compared to processing via transcription-coupled pathways, and that the processing of these adducts into DNA breaks is independent of topoisomerase II. It has previously been shown that cells deficient in homologous recombination (HR) are hypersensitive to adduct forming treatments. Given that anthracycline-DNA adducts, whilst not true crosslinks, are associated with both DNA strands, the role of ICL repair pathways was investigated. Mus81 is a structure specific nuclease implicated in Holliday junction resolution and the resolution of branched DNA formed by stalled replication forks. We now show that ICL repair deficient cells (Mus81 -/-) are hypersensitive to anthracycline-DNA adducts and ET-743, a compound which causes a chemically similar type of DNA damage. Further analysis of this mechanism showed that Mus81 does not appear to cause DNA breaks resulting from either anthracycline- or ET743-DNA adducts. This suggests Mus81 processes these novel forms of DNA damage in a fundamentally different way compared to the processing of classical covalent crosslinks. Improved understanding of the role of DNA repair in response to such adducts may lead to more effective chemotherapy for patients with BRCA1/2 mutations and other HR deficiencies.
机译：蒽环类化学疗法的特征是拓扑异构酶II的毒性，但是许多蒽环类药物（包括阿霉素）也能够形成药物-DNA加合物。蒽环霉素-DNA加合物对细胞而言是一个不寻常的障碍，因为它们共价连接至一条DNA链，并通过氢键结合至另一条链而稳定。我们现在表明，在循环细胞中，与通过转录偶联途径进行加工相比，通过DNA复制进行蒽环加合物的加工似乎占主导地位，并且这些加合物加工成DNA断裂与拓扑异构酶II无关。先前已经证明缺乏同源重组（HR）的细胞对加合物形成处理高度敏感。考虑到蒽环霉素-DNA加合物（虽然不是真正的交联）与两条DNA链都相关，所以研究了ICL修复途径的作用。 Mus81是一种结构特异的核酸酶，与霍利迪结的分辨率和停滞的复制叉形成的分支DNA的分辨率有关。现在，我们显示ICL修复缺陷细胞（Mus81-/-）对蒽环类DNA加合物和ET-743（一种引起化学上相似类型的DNA损伤的化合物）高度敏感。对该机理的进一步分析表明，Mus81似乎不会引起由蒽环类或ET743-DNA加合物引起的DNA断裂。这表明与经典共价交联的处理相比，Mus81以根本不同的方式处理这些新型形式的DNA损伤。对DNA修复对此类加合物的反应的理解的进一步深入，可能会导致具有BRCA1 / 2突变和其他HR缺陷的患者接受更有效的化疗。

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