The stability of a model substrate for topoisomerase 1-mediated DNA religation depends on the presence of mismatched base pairs.
The stability of a model substrate for topoisomerase 1-mediated DNA religation depends on the presence of mismatched base pairs.
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DOI：
10.4061/2011/631372
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发表时间：
2011
影响因子：
2.3
通讯作者：
Marky LA
中科院分区：
文献类型：
--
作者：
Gmeiner WH;Salsbury F Jr;Olsen CM;Marky LA
拓扑异构酶1 （Top1）通过形成共价切割复合体来调节DNA的超螺旋度。核苷类似物在DNA双链相对于Top1切割位点的+1位置上的取代抑制了DNA的重组。top1介导的宗教效率的降低有助于氟嘧啶和吉西他滨等广泛使用的抗癌药物的抗癌活性。在本研究中，我们报告了+1位置不匹配的碱基对破坏了模型Top1切割复合物形成的双工DNA组分的稳定性，即使一个双工组分不直接包含不匹配的碱基对。分子动力学模拟表明G-dU和G-FdU错配碱基对增加了Top1切割位点的柔韧性，并影响了宗教反应发生所需区域之间的耦合。这些结果表明，将dT类似物取代到非剪切链的+1位置会改变DNA的稳定性和柔韧性，从而降低了top1介导的DNA置换效率。这些作用是DNA双链固有的，不需要形成Top1:DNA复合体。这些结果为核苷酸类似物取代抑制top1介导的DNA虔诚提供了生物物理理论依据。
Topoisomerase 1 (Top1) enzymes regulate DNA superhelicity by forming covalent cleavage complexes that undergo controlled rotation. Substitution of nucleoside analogs at the +1 position of the DNA duplex relative to the Top1 cleavage site inhibits DNA religation. The reduced efficiency for Top1-mediated religation contributes to the anticancer activity of widely used anticancer drugs including fluoropyrimidines and gemcitabine. In the present study, we report that mismatched base pairs at the +1 position destabilize the duplex DNA components for a model Top1 cleavage complex formation even though one duplex component does not directly include a mismatched base pair. Molecular dynamics simulations reveal G-dU and G-FdU mismatched base pairs, but not a G-T mismatched base pair, increase flexibility at the Top1 cleavage site, and affect coupling between the regions required for the religation reaction to occur. These results demonstrate that substitution of dT analogs into the +1 position of the non-scissile strand alters the stability and flexibility of DNA contributing to the reduced efficiency for Top1-mediated DNA religation. These effects are inherent in the DNA duplex and do not require formation of the Top1:DNA complex. These results provide a biophysical rationale for the inhibition of Top1-mediated DNA religation by nucleotide analog substitution.