DNA sequence selectivity of human topoisomerase I-mediated DNA cleavage induced by camptothecin.
DNA sequence selectivity of human topoisomerase I-mediated DNA cleavage induced by camptothecin.
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喜树碱诱导的人拓扑异构酶 I 介导的 DNA 切割的 DNA 序列选择性。
DOI：
10.1002/pro.138
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Yang,Danzhou
中科院分区：
文献类型：
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作者：
Punchihewa,Chandanamali;Carver,Megan;Yang,Danzhou
为了探讨喜树碱抑制缺氧诱导因子（HIF-1）的机制，我们研究了人拓扑异构酶I结合和切割HIF-1反应元件（HRE）的能力，HRE含有已知的喜树碱介导的拓扑异构酶I切割位点5′-TG。我们观察到，人拓扑异构酶I和拓扑替康对5′-TG的选择在很大程度上取决于特定的侧翼序列，并且−2位（切割发生在−1和+1之间）的G的存在阻止了HRE位点成为这种切割的首选位点。此外，−2 T/A的存在可以在不太优选的TC或TA位点诱导切割。然而，在缺乏更优选的位点的情况下，HRE位点显示在托泊替康存在下被人拓扑异构酶I切割。因此，这意味着−2碱基对喜树碱介导的Topo I切割位点的选择具有显著影响，这可以克服+1G的偏好。虽然已知切割位点识别是基于跨越切割位点的几个碱基的协同作用，但先前尚未认识到单个碱基的这种决定性作用。DNA和拓扑异构酶I之间可能的碱基特异性相互作用可能是这种序列选择性的原因。
In probing the mechanism of inhibition of hypoxia inducible factor (HIF‐1) by campothecins, we investigated the ability of human topoisomerase I to bind and cleave HIF‐1 response element (HRE), which contains the known camptothecin‐mediated topoisomerase I cleavage site 5′‐TG. We observed that the selection of 5′‐TG by human topoisomerase I and topotecan depends to a large extent on the specific flanking sequences, and that the presence of a G at the −2 position (where cleavage occurs between −1 and +1) prevents the HRE site from being a preferred site for such cleavage. Furthermore, the presence of −2 T/A can induce the cleavage at a less preferred TC or TA site. However, in the absence of a more preferred site, the HRE site is shown to be cleaved by human topoisomerase I in the presence of topotecan. Thus, it is implied that the −2 base has a significant influence on the selection of the camptothecin‐mediated Topo I cleavage site, which can overcome the preference for +1G. While the cleavage site recognition has been known to be based on the concerted effect of several bases spanning the cleavage site, such a determining effect of an individual base has not been previously recognized. A possible base‐specific interaction between DNA and topoisomerase I may be responsible for this sequence selectivity.