Mechanism of transcriptional stalling at cisplatin-damaged DNA
Mechanism of transcriptional stalling at cisplatin-damaged DNA
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DOI：
10.1038/nsmb1314
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发表时间：
2007-12-01
影响因子：
16.8
通讯作者：
Cramer, Patrick
中科院分区：
文献类型：
--
作者：
Damsma, Gerke E.;Alt, Aaron;Cramer, Patrick
抗癌药物顺铂形成1,2 - d(GpG) DNA链内交联（顺铂损伤），使RNA聚合酶II（Pol II）停滞并触发转录偶联的DNA修复。在此，我们对Pol II在DNA模板中的顺铂损伤处停滞进行结构 - 功能分析。Pol II停滞是由于一个易位障碍，该障碍阻止损伤被递送到活性位点。AMP错掺入发生在该障碍处以及无碱基位点，这表明它是根据已知的DNA聚合酶的“A规则”由非模板合成产生的。Pol II能够绕过人为置于易位障碍之外的顺铂损伤，即使存在G - A错配也是如此。因此，该障碍防止了转录突变。这种停滞机制不同于Pol II在光损伤处的停滞机制，后者涉及将损伤递送到活性位点以及以损伤为模板的错掺入从而阻断转录。
The anticancer drug cisplatin forms 1,2-d(GpG) DNA intrastrand cross-links ( cisplatin lesions) that stall RNA polymerase II (Pol II) and trigger transcription-coupled DNA repair. Here we present a structure-function analysis of Pol II stalling at a cisplatin lesion in the DNA template. Pol II stalling results from a translocation barrier that prevents delivery of the lesion to the active site. AMP misincorporation occurs at the barrier and also at an abasic site, suggesting that it arises from nontemplated synthesis according to an 'A-rule' known for DNA polymerases. Pol II can bypass a cisplatin lesion that is artificially placed beyond the translocation barrier, even in the presence of a G. A mismatch. Thus, the barrier prevents transcriptional mutagenesis. The stalling mechanism differs from that of Pol II stalling at a photolesion, which involves delivery of the lesion to the active site and lesion-templated misincorporation that blocks transcription.