Nucleotide selectivity opposite a benzo[a]pyrene-derived N2-dG adduct in a Y-family DNA polymerase: a 5'-slippage mechanism.
Nucleotide selectivity opposite a benzo[a]pyrene-derived N2-dG adduct in a Y-family DNA polymerase: a 5'-slippage mechanism.
复制标题
Y 家族 DNA 聚合酶中与苯并[a]芘衍生的 N2-dG 加合物相反的核苷酸选择性：5-滑移机制。
DOI：
10.1021/bi701839q
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发表时间：
2008
期刊：
影响因子：
2.9
通讯作者：
Broyde,Suse
中科院分区：
文献类型：
--
作者：
Xu,Pingna;Oum,Lida;Geacintov,NicholasE;Broyde,Suse
Y家族DNA聚合酶Dpo 4来自于古细菌硫磺硫化叶菌（Sulfolobus solfataricus），是DinB家族的成员，也包含人类Pol κ。它有一个宽敞的活性位点，可以同时容纳两个模板碱基，其中一个被传入的dNTP跳过。对与苯并[a]芘衍生的N2-dG加合物10 S（+）-trans-anti-[BP]-N2-dG（[BP]G*）相对的单个dNTP插入的分析表明，在TG 1 * G2序列背景下，引入的dATP明显优于其他三种dNTP。分子建模和动力学模拟进行解释这一实验观察分子水平上。建模研究表明，实验观察到的dATP插入的显着偏好可以从两个可能的dATP掺入模式。dATP可以在加合物G1* 的5′侧插入T的对面，使用不寻常的5′-滑动模式，其中未加合的G2而不是G1* 被跳过，产生-1缺失。此外，dATP可与加合物相对地错误掺入。5′-滑动模式通常在病变的基底3′与内收基底相同的情况下更容易发生。
The Y-family DNA polymerase Dpo4, from the archaeon bacterium Sulfolobus solfataricus, is a member of the DinB family, which also contains human Pol κ. It has a spacious active site that can accommodate two templating bases simultaneously, with one of them skipped by the incoming dNTP. Assays of single dNTP insertion opposite a benzo[a]pyrene-derivedN2-dG adduct, 10S(+)-trans-anti-[BP]-N2-dG ([BP]G*), reveal that an incoming dATP is significantly preferred over the other three dNTPs in the TG1*G2sequence context. Molecular modeling and dynamics simulations were carried out to interpret this experimental observation on a molecular level. Modeling studies suggest that the significant preference for dATP insertion observed experimentally can result from two possible dATP incorporation modes. The dATP can be inserted opposite the T on the 5′ side of the adduct G1*, using an unusual 5′-slippage pattern, in which the unadducted G2, rather than G1*, is skipped, to produce a −1 deletion. In addition, the dATP can be misincorporated opposite the adduct. The 5′-slippage pattern may be generally facilitated in cases where the base 3′ to the lesion is the same as the adducted base.