Specificity of platinum-DNA adduct repair
Specificity of platinum-DNA adduct repair
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DOI：
10.1016/s0162-0134(99)00149-x
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发表时间：
1999-10-01
影响因子：
3.9
通讯作者：
Vaisman, A
中科院分区：
文献类型：
--
作者：
Chaney, SG;Vaisman, A
对顺铂和卡铂具有抗性的细胞系通常保留对具有不同载体配体的铂络合物的敏感性（例如，奥沙利铂和JM 216）。HeLa细胞提取物被证明切除顺铂，奥沙利铂，和JM 216加合物具有相同的效率，这表明核苷酸切除修复并不有助于铂耐药的载体-配体特异性。我们以前已经表明，在体内复制旁路的程度是由铂加合物的载体配体的影响。复制旁路的特异性可以通过催化跨损伤合成经过Pt-DNA加合物的DNA聚合酶复合物、通过去除与Pt-DNA加合物相对的新合成的DNA的错配修复系统和/或通过结合到Pt-DNA加合物并阻断跨损伤合成的DNA损伤识别蛋白来确定。在含有位点特异性放置的顺铂、奥沙利铂或JM 216 Pt-GG加合物的DNA模板上的引物延伸揭示，真核DNA聚合酶β、ζ、γ和HIV-1 RT对跨损伤合成具有类似的特异性，而不是Pt-DNA加合物（奥沙利铂大于或等于顺铂> JM 216）。此外，错配修复蛋白hMSH 6和hMLH 1的缺陷导致顺铂加合物的复制旁路增加，但奥沙利铂加合物没有。最后，在已知识别顺铂损伤DNA的HMG 1存在下进行的引物延伸测定显示，HMG 1对跨损伤合成的抑制也依赖于Pt-DNA加合物的载体配体（顺铂>奥沙利铂= JM 216）。这些研究表明，DNA聚合酶，错配修复系统和损伤识别蛋白都可以赋予特异性复制旁路的Pt-DNA加合物。复制旁路，反过来，可能会影响耐药的载体-配体特异性。（C）1999年Elsevier Science Inc. All rights reserved.
Cell lines with resistance to cisplatin and carboplatin often retain sensitivity to platinum complexes with different carrier ligands (e.g., oxaliplatin and JM216). HeLa cell extracts were shown to excise cisplatin, oxaliplatin, and JM216 adducts with equal efficiency, suggesting that nucleotide excision repair does not contribute to the carrier-ligand specificity of platinum resistance. We have shown previously that the extent of replicative bypass in vivo is influenced by the carrier ligand of the platinum adducts. The specificity of replicative bypass may be determined by the DNA polymerase complexes that catalyze translesion synthesis past Pt-DNA adducts, by the mismatch-repair system that removes newly synthesized DNA opposite Pt-DNA adducts, and/or by DNA damage-recognition proteins that bind to the Pt-DNA adducts and block translesion synthesis. Primer extension on DNA templates containing site-specifically placed cisplatin, oxaliplatin, or JM216 Pt-GG adducts revealed that the eukaryotic DNA polymerases beta, zeta, gamma and HIV-1 RT had a similar specificity for translesion synthesis past Pt-DNA adducts (oxaliplatin greater than or equal to cisplatin > JM216). In addition, defects in the mismatch-repair proteins hMSH6 and hMLH1 led to increased replicative bypass of cisplatin adducts, but not of oxaliplatin adducts. Finally, primer extension assays performed in the presence of HMG1, which is known to recognize cisplatin-damaged DNA, revealed that inhibition of translesion synthesis by HMG1 also depended on the carrier ligand of the Pt-DNA adduct (cisplatin > oxaliplatin = JM216). These studies show that DNA polymerases, the mismatch-repair system and damage-recognition proteins can all impart specificity to replicative bypass of Pt-DNA adducts. Replicative bypass, in turn, may influence the carrier-ligand specificity of resistance. (C)1999 Elsevier Science Inc. All rights reserved.