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首页> 外文期刊>Journal of Molecular Biology >Structural Basis for Human DNA Polymerase Kappa to Bypass Cisplatin Intrastrand Cross-Link (Pt-GG) Lesion as an Efficient and Accurate Extender
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Structural Basis for Human DNA Polymerase Kappa to Bypass Cisplatin Intrastrand Cross-Link (Pt-GG) Lesion as an Efficient and Accurate Extender

机译：人体DNA聚合酶Kappa的结构基础绕过顺铂卵链状链路（PT-GG）病变作为高效和准确的扩展器

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摘要

Cisplatin (cis-diamminedichloroplatinum) is a common chemotherapeutic drug that reacts with the N7 atoms of adjacent guanines in DNA to form the Pt-1,2-d(GpG) intrastrand cross-link (Pt-GG), a major product to block DNA replication. Translesion DNA synthesis has been implicated in chemoresistance during cisplatin treatment of cancer due to Pt-GG lesion bypass. Gene knockdown studies in human cells have indicated a role for pol kappa during translesion synthesis of the Pt-GG lesion. However, the bypass activity of pol kappa with cisplatin lesions has not been well characterized. In this study, we investigated pol kappa's ability to bypass Pt-GG lesion in vitro and determined two crystal structures of pol kappa in complex with Pt-GG DNA. The ternary complex structures represent two consecutive stages of lesion bypass: nucleotide insertion opposite the 5'G (Pt-GG2) and primer extension immediately after the lesion (Pt-GG3). Our biochemical data showed that pol kappa is very efficient and accurate in extending DNA primers after the first G of the Pt-GG lesion. The structures demonstrate that the efficiency and accuracy is achieved by stably accommodating the bases with the cisplatin adduct in the active site for proper Watson-Crick base pairing with the incoming nucleotide in both the second insertion and post-insertion complexes. Our studies suggest that pol kappa works as an extender for efficient replication of the Pt-GG lesion in cells. This work holds promise for considering pol kappa, along with pol eta, as potential targets for drug design, which together could improve the efficacy of cisplatin treatment for cancer therapy. (C) 2018 Elsevier Ltd. All rights reserved.
机译：顺铂（CIS-DIAMINMOLICHLOLOPLATINUM）是一种常见的化学治疗药物，其与DNA中的相邻鸟嘌呤的N7原子反应，以形成PT-1,2-D（GPG）卵体内联串（PT-GG），是阻塞的主要产物DNA复制。 Translesion DNA合成在Cisplatin治疗引起的PT-GG病变旁路时涉及化学抑制。人体细胞的基因敲低研究表明PT-GG病变的翻转合成过程中Pol Kappa的作用。然而，具有顺铂病变的Pol Kappa的旁路活性并未详细表征。在这项研究中，我们研究了Pol Kapp在体外绕过PT-GG病变的能力，并用PT-GG DNA复合物中的POL Kappa的两种晶体结构。三元复合结构代表病变旁路的两个连续阶段：在病变后立即与5'g（PT-GG2）和引物延伸相对的核苷酸插入（PT-GG3）。我们的生化数据显示，在PT-GG病变之后在延长DNA引物中，POL Kappa非常高效，准确。该结构表明，通过在第二插入和插入后复合物中与进入的核苷酸稳定地将基座与活性位点中的顺铂加合物稳定地将基座稳定地达到效率和准确性。我们的研究表明，POL Kappa用作扩展器，以便在细胞中有效复制pt-gg病变。这项工作持有希望考虑Pol Kappa以及Pol ETA，作为药物设计的潜在目标，它们共同可以提高顺铂治疗对癌症治疗的疗效。 （c）2018年elestvier有限公司保留所有权利。

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