An intrastrand d(GpG) platinum crosslink in duplex M13 DNA is refractory to repair by human cell extracts.
An intrastrand d(GpG) platinum crosslink in duplex M13 DNA is refractory to repair by human cell extracts.
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DOI：
10.1073/pnas.89.22.10772
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发表时间：
1992-11
影响因子：
11.1
通讯作者：
David Edmund Szymkowski;K. Yarema;J. Essigmann;S. Lippard;R. Wood
中科院分区：
文献类型：
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作者：
David Edmund Szymkowski;K. Yarema;J. Essigmann;S. Lippard;R. Wood
我们已经研究了人类细胞提取物修复癌症化疗剂顺二氨二氯铂（II）引起的最常见的DNA加合物的能力。合成了在特定位点具有链内d（GpG）交联的环状DNA双链体。人类细胞提取物不能诱导修复合成的29个碱基对区域涵盖的加合物或在相邻区域。相同的浸提液可以修复相似位置的单个确定的2-乙酰氨基芴损伤。当含有铂加合物的分子被大肠杆菌UvrABC酶切割时，人类细胞提取物可以在受损部位进行修复合成，这表明人类酶无法在d（GpG）交联附近形成切口，但一旦形成切口就可以完成修复。这一结果表明，大多数修复合成的DNA损伤与多个顺二氨二氯铂（II）加合物发生在病变以外的主要d（GpG）交联。这些数据支持这样的想法，即顺式二氨二氯铂（II）的临床有效性可能是由于这种药物引起的主要DNA加合物的修复效率低下。
We have examined the ability of human cell extracts to repair the most frequent DNA adduct caused by the cancer chemotherapeutic agent cis-diamminedichloroplatinum(II). A circular DNA duplex with an intrastrand d(GpG) crosslink positioned at a specific site was synthesized. Human cell extracts were unable to induce repair synthesis in a 29-base-pair region encompassing the adduct or in adjacent regions. The same extracts could repair a single defined 2-acetylaminofluorene lesion in a similar location. When molecules containing the platinum adduct were cleaved by Escherichia coli UvrABC enzyme, human cell extracts could perform repair synthesis at the damaged site, suggesting that human enzymes fail to make incisions near the d(GpG) crosslink but can complete repair once incisions are made. This result indicates that most repair synthesis in DNA damaged with multiple cis-diamminedichloroplatinum(II) adducts takes place at lesions other than the predominant d(GpG) crosslink. These data support the idea that the clinical effectiveness of cis-diamminedichloroplatinum(II) may be explained by the inefficient repair of the major DNA adduct caused by this drug.