Thermodynamic consequences of the hyperoxidized guanine lesion guanidinohydantoin in duplex DNA.
Thermodynamic consequences of the hyperoxidized guanine lesion guanidinohydantoin in duplex DNA.
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DOI：
10.1021/tx300190a
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发表时间：
2012-08-20
影响因子：
4.1
通讯作者：
Delaney S
中科院分区：
文献类型：
--
作者：
Yennie CJ;Delaney S
胍基乙内酰脲（Guanidinohydantoin，Gh）是由8-oxo-7，8-dihydroguanine（8-oxoG）氧化产生的一种过氧化DNA损伤。先前的工作已经表明，Gh在体外和体内都具有潜在的致突变性，编码G → T和G → C颠换突变。在这项工作中，通过圆二色性分析表明，Gh损伤并没有显着改变15-mer双链体的整体结构，并且DNA保持在B型。然而，我们发现Gh导致热稳定性的大幅降低，相对于未修饰的双链体对照，使双链体解链温度降低约17 °C。使用光学熔融分析和差示扫描量热法还确定了描述双重熔融的热力学参数。我们发现，Gh病变导致双链体的稳定性急剧下降。这种双链体的不稳定性在某种程度上被熵稳定化所缓和，但相对于没有DNA损伤的对照，Gh导致双链体的热力学稳定性总体下降，ΔΔG°为−7 kcal/mol。这些结果有助于我们理解的后果G的过氧化，并提供洞察如何的热和热力学不稳定引起的Gh可能会影响复制和/或修复的病变。
Guanidinohydantoin (Gh) is a hyperoxidized DNA lesion produced by oxidation of 8-oxo-7,8-dihydroguanine (8-oxoG). Previous work has shown that Gh is potently mutagenic both in vitro and in vivo coding for G → T and G → C transversion mutations. In this work, analysis by circular dichroism shows that the Gh lesion does not significantly alter the global structure of a 15-mer duplex, and that the DNA remains in the B-form. However, we find that Gh causes a large decrease in the thermal stability, decreasing the duplex melting temperature by ~ 17 °C relative to an unmodified duplex control. Using optical melting analysis and differential scanning calorimetry the thermodynamic parameters describing duplex melting were also determined. We find that the Gh lesion causes a dramatic decrease in the enthalpic stability of the duplex. This enthalpic destabilization is somewhat tempered by entropic stabilization yet Gh results in an overall decrease in thermodynamic stability of the duplex relative to a control which lacks DNA damage, with a ΔΔG° of −7 kcal/mol. These results contribute to our understanding of the consequences of hyperoxidation of G and provide insight into how the thermal and thermodynamic destabilization caused by Gh may influence replication and/or repair of the lesion.
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