Effect of a monofunctional phenanthriplatin-DNA adduct on RNA polymerase II transcriptional fidelity and translesion synthesis.
Effect of a monofunctional phenanthriplatin-DNA adduct on RNA polymerase II transcriptional fidelity and translesion synthesis.
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DOI：
10.1021/ja405475y
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发表时间：
2013-09-04
影响因子：
15
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Kellinger MW;Park GY;Chong J;Lippard SJ;Wang D
铂类抗癌药物的转录抑制作用是其作用机制的重要组成部分。菲铂是一种顺铂衍生物，含有菲啶代替其中一种氯配体，在DNA上形成高效单功能加合物，其抗癌活性的结构和谱与母体药物不同。了解菲铂对RNA聚合酶II（Pol II）（主要的细胞转录机器组件）的正常功能的DNA损伤的功能后果，是阐明其作用机制的重要一步。在这项研究中，我们提出了第一个系统的机制研究，解决了一个位点特异性的菲铂-DNA d（G）单功能加合物如何影响Pol II的延伸和转录保真度检查点步骤。Pol II处理的菲铂病变显着不同，从典型的顺铂DNA 1，2-d（GpG）链内交联。大多数Pol II延伸复合物在成功添加CTP后以无错误的方式与菲铂-dG加合物相对停滞，其中CTP掺入的特异性与模板上未受损的dG基本相同。Pol II的一小部分经历了缓慢的、容易出错的菲铂-dG损伤旁路，这类似于DNA聚合酶，其类似地在DNA损伤位点从高保真复制DNA加工（无错误）切换到低保真跨损伤DNA合成（容易出错）。这些结果首次深入了解了Pol II转录机制如何处理单功能菲铂抗癌药物候选药物中最丰富的DNA损伤，并丰富了我们对Pol II转录保真度维持、损伤绕过和转录衍生突变的总体理解。由于目前对单功能DNA损伤金属药物的兴趣，这些结果可能与药物无机化学界正在开发的广谱下一代抗癌药物有关。
Transcription inhibition by platinum anticancer drugs is an important component of their mechanism of action. Phenanthriplatin, a cisplatin derivative containing phenanthridine in place of one of the chloride ligands, forms highly potent monofunctional adducts on DNA having a structure and spectrum of anticancer activity distinct from those of the parent drug. Understanding the functional consequences of DNA damage by phenanthriplatin for the normal functions of RNA polymerase II (Pol II), the major cellular transcription machinery component, is an important step toward elucidating its mechanism of action. In this study, we present the first systematic mechanistic investigation that addresses how a site-specific phenanthriplatin-DNA d(G) monofunctional adduct affects the Pol II elongation and transcriptional fidelity checkpoint steps. Pol II processing of the phenanthriplatin lesion differs significantly from that of the canonical cisplatin DNA 1,2-d(GpG) intrastrand cross-link. A majority of Pol II elongation complexes stall after successful addition of CTP opposite the phenanthriplatin-dG adduct in an error-free manner, with specificity for CTP incorporation being essentially the same as for undamaged dG on the template. A small portion of Pol II undergoes slow, error-prone bypass of the phenanthriplatin-dG lesion, which resembles DNA polymerases that similarly switch from high-fidelity replicative DNA processing (error-free) to low-fidelity translesion DNA synthesis (error-prone) at DNA damage sites. These results provide the first insights into how the Pol II transcription machinery processes the most abundant DNA lesion of the monofunctional phenanthriplatin anticancer drug candidate and enrich our general understanding of Pol II transcription fidelity maintenance, lesion bypass, and transcription-derived mutagenesis. Because of the current interest in monofunctional, DNA-damaging metallodrugs, these results are of likely relevance to a broad spectrum of next-generation anticancer agents being developed by the medicinal inorganic chemistry community.