Structural Basis for Promutagenicity of 8-Halogenated Guanine*
Structural Basis for Promutagenicity of 8-Halogenated Guanine*
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8-卤代鸟嘌呤促诱变的结构基础*
DOI：
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发表时间：
2014
影响因子：
4.8
通讯作者：
Seongmin Lee
中科院分区：
文献类型：
--
作者：
M. Koag;Kyung‐Jin Min;Seongmin Lee
背景：8-卤代鸟嘌呤是一种前致突变损伤，在DNA复制过程中促进鸟嘌呤插入损伤对面。结果：8-溴鸟嘌呤在polβ的活性部位与G形成Hoogsteen碱基配对，与C形成Watson-Crick碱基配对。结论：8-溴鸟嘌呤能很好地容纳在polβ的新生碱基对结合口袋中。意义：我们的结构研究为潜在的G到C突变提供了见解。8-卤代鸟嘌呤（haloG）是炎症过程中由反应性卤素物质形成的主要DNA加合物，是一种促突变损伤，其通过各种DNA聚合酶促进损伤对面的G的错误掺入。目前，这种错误纳入的结构基础尚不清楚。为了深入了解聚合酶错误掺入haloG的机制，我们测定了7种与8-溴鸟嘌呤（BrG）DNA结合的人DNA聚合酶β（polβ）的X射线结构。我们确定了polβ与引入的不可水解的dGTP或dCTP类似物与模板BrG配对的两种预催化三元复合物结构。我们还确定了polβ与含BrG·C/T的DNA在插入后和延伸后位点形成的五种二元复合物结构。在BrG·dGTP三元结构中，BrG采用顺式构象并与引入的dGTP类似物形成Hoogsteen碱基配对。在BrG·dCTP三元结构中，BrG采用反构象，并与引入的dCTP类似物形成Watson-Crick碱基配对。此外，polβ二元后延伸结构显示Hoogsteen BrG·G碱基对和Watson-Crick BrG·C碱基对。总之，含卤代G的DNA与蛋白质结合的第一个结构表明BrG·G和BrG·C碱基对都容纳在polβ的活性位点中。我们的结构表明，G和C8修饰的G之间的Hoogsteen型碱基配对可以容纳在DNA聚合酶的活性位点，促进G到C的突变。
Background: 8-Halogenated guanine is a promutagenic lesion that promotes insertion of guanine opposite the lesion during DNA replication. Results: 8-Bromoguanine forms Hoogsteen base pairing with G and Watson-Crick base pairing with C in the active site of polβ. Conclusion: 8-Bromoguanine is well accommodated in the nascent base pair binding pocket of polβ. Significance: Our structural studies provide insights into potential G to C mutations. 8-Halogenated guanine (haloG), a major DNA adduct formed by reactive halogen species during inflammation, is a promutagenic lesion that promotes misincorporation of G opposite the lesion by various DNA polymerases. Currently, the structural basis for such misincorporation is unknown. To gain insights into the mechanism of misincorporation across haloG by polymerase, we determined seven x-ray structures of human DNA polymerase β (polβ) bound to DNA bearing 8-bromoguanine (BrG). We determined two pre-catalytic ternary complex structures of polβ with an incoming nonhydrolyzable dGTP or dCTP analog paired with templating BrG. We also determined five binary complex structures of polβ in complex with DNA containing BrG·C/T at post-insertion and post-extension sites. In the BrG·dGTP ternary structure, BrG adopts syn conformation and forms Hoogsteen base pairing with the incoming dGTP analog. In the BrG·dCTP ternary structure, BrG adopts anti conformation and forms Watson-Crick base pairing with the incoming dCTP analog. In addition, our polβ binary post-extension structures show Hoogsteen BrG·G base pair and Watson-Crick BrG·C base pair. Taken together, the first structures of haloG-containing DNA bound to a protein indicate that both BrG·G and BrG·C base pairs are accommodated in the active site of polβ. Our structures suggest that Hoogsteen-type base pairing between G and C8-modified G could be accommodated in the active site of a DNA polymerase, promoting G to C mutation.
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影响因子：
56.9
作者：
SAWAYA, MR;PELLETIER, H;KRAUT, J
通讯作者：
KRAUT, J
影响因子：
5.7
作者：
Ravelli, RBG;Leiros, HKS;McSweeney, S
通讯作者：
McSweeney, S
影响因子：
56.9
作者：
PELLETIER, H;SAWAYA, MR;KRAUT, J
通讯作者：
KRAUT, J
影响因子：
15.9
作者：
Meira, Lisiane B.;Bugni, James M.;Samson, Leona D.
通讯作者：
Samson, Leona D.
影响因子：
56.9
作者：
WEISS, SJ;TEST, ST;REGIANI, S
通讯作者：
REGIANI, S