Mazumder A, Perrin D M, Watson K J, Sigman D S
Department of Biological Chemistry, School of Medicine, University of California, Los Angeles 90024-1570.
Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8140-4. doi: 10.1073/pnas.90.17.8140.
The kinetically component open complexes formed at prokaryotic and eukaryotic transcription start sites are efficiently nicked by the chemical nuclease activity of the 2:1 1,10-phenanthroline-copper(I) complex [(OP)2Cu+] and hydrogen peroxide. This reaction specificity has been attributed to the creation of a binding site(s) for redox-active tetrahedral (OP)2Cu+ when RNA polymerase form productive complexes with promoters. This proposal has been confirmed for the Escherichia coli lac UV-5 promoter by the demonstration that the 2:1 2,9-dimethyl-1,10-phenanthroline-copper(I) complex [(Me2OP)2Cu+], a redox-inactive isostere of (OP)2-Cu+, protects the transcription start site from scission by the chemical nuclease activity. (Me2OP)2Cu+ is also an effective inhibitor of transcription. The inhibition of transcription and the protection from scission of the open complex by (OP)2Cu+ exhibit the same dependence on the concentration of (Me2OP)2Cu+. This redox- and exchange-stable species is a previously undescribed transcription inhibitor that binds to a site generated by the interaction of RNA polymerase with the promoter. Unlike the intercalating agent proflavine, which is also an effective transcription inhibitor, it does not displace the enzyme from the promoter. The ability of (Me2OP)2Cu+ to inhibit transcription may be partially responsible for its potent cytotoxicity.
在原核生物和真核生物转录起始位点形成的动力学组分开放复合物，能被2:1的1,10 - 菲咯啉 - 铜（I）配合物[（OP）₂Cu⁺]与过氧化氢的化学核酸酶活性有效地切口。这种反应特异性归因于当RNA聚合酶与启动子形成生产性复合物时，为氧化还原活性四面体（OP）₂Cu⁺创造了一个结合位点。通过证明2:1的2,9 - 二甲基 - 1,10 - 菲咯啉 - 铜（I）配合物[（Me₂OP）₂Cu⁺]（（OP）₂Cu⁺的氧化还原惰性等排体）能保护转录起始位点免受化学核酸酶活性的切割，这一推测已在大肠杆菌乳糖UV - 5启动子上得到证实。（Me₂OP）₂Cu⁺也是一种有效的转录抑制剂。（OP）₂Cu⁺对转录的抑制作用以及对开放复合物切割的保护作用，对（Me₂OP）₂Cu⁺浓度表现出相同的依赖性。这种氧化还原和交换稳定的物质是一种先前未描述的转录抑制剂，它与RNA聚合酶和启动子相互作用产生的位点结合。与也是有效转录抑制剂的嵌入剂原黄素不同，它不会将酶从启动子上置换下来。（Me₂OP）₂Cu⁺抑制转录的能力可能部分导致了其强大的细胞毒性。
