Role of base flipping in specific recognition of damaged DNA by repair enzymes
Role of base flipping in specific recognition of damaged DNA by repair enzymes
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DOI：
10.1016/s0022-2836(02)00999-3
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发表时间：
2002-11-08
影响因子：
5.6
通讯作者：
Osman, R
中科院分区：
文献类型：
--
作者：
Fuxreiter, M;Luo, M;Osman, R
DNA修复酶在损伤识别过程中诱导碱基翻转。核酸内切酶V启动DNA中由UV辐射产生的顺式，顺式胸腺嘧啶二聚体（TD）的修复。已知这种酶可以将损伤对面的碱基翻转到蛋白质内的非特异性结合口袋中。尿嘧啶DNA糖基化酶从G（.）通过最初将其翻转到酶中高度特异性的口袋中，使DNA中的U错配。利用分子动力学模拟方法研究了DNA损伤模型和未损伤模型的碱基翻转对特异性识别的贡献。弯曲和打开角度的分布的分析表明，增强的碱基翻转起源于受损DNA的柔性增加和关闭和打开状态之间的能量差的降低。受损DNA的灵活性增加，导致DNA更容易受到酶诱导的扭曲，这降低了碱基翻转的障碍。使用平均力表示的潜在的基地翻转过程的自由能分布。含TD的DNA的屏障比未受损DNA中的屏障低2.5 kcal mol（-1），而尿嘧啶翻转的屏障比未受损DNA中胞嘧啶碱基翻转的屏障低11.6 kcal mol（-1）。碱基翻转的最终势垒约为10 kcal mol（-1），使得碱基翻转的速率与DNA上蛋白质的线性扫描速率相似。这些结果表明，基于降低碱基翻转屏障的损伤识别可以为其他DNA修复酶提供一般机制。(C)2002爱思唯尔科技有限公司版权所有。
DNA repair enzymes induce base flipping in the process of damage recognition. Endonuclease V initiates the repair of cis, syn thymine dimers (TD) produced in DNA by UV radiation. The enzyme is known to flip the base opposite the damage into a non-specific binding pocket inside the protein. Uracil DNA glycosylase removes a uracil base from G(.)U mismatches in DNA by initially flipping it into a highly specific pocket in the enzyme. The contribution of base flipping to specific recognition has been studied by molecular dynamics simulations on the closed and open states of undamaged and damaged models of DNA. Analysis of the distributions of bending and opening angles indicates that enhanced base flipping originates in increased flexibility of the damaged DNA and the lowering of the energy difference between the closed and open states. The increased flexibility of the damaged DNA gives rise to a DNA more susceptible to distortions induced by the enzyme, which lowers the barrier for base flipping. The free energy profile of the base-flipping process was constructed using a potential of mean force representation. The barrier for TD-containing DNA is 2.5 kcal mol(-1) lower than that in the undamaged DNA, while the barrier for uracil flipping is 11.6 kcal mol(-1) lower than the barrier for flipping a cytosine base in the undamaged DNA. The final barriers for base flipping are approximately 10 kcal mol(-1), making the rate of base flipping similar to the rate of linear scanning of proteins on DNA. These results suggest that damage recognition based on lowering the barrier for base flipping can provide a general mechanism for other DNA-repair enzymes. (C) 2002 Elsevier Science Ltd. All rights reserved.