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首页> 外文期刊>Biochemistry >Efficiency of Incision of an AP Site within Clustered DNA Damage by the Major Human AP Endonuclease
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Efficiency of Incision of an AP Site within Clustered DNA Damage by the Major Human AP Endonuclease

机译：人类主要AP内切核酸酶在簇状DNA损伤内切开AP位点的效率

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摘要

A major DNA lesion induced by ionizing radiation and formed on removal of oxidized base lesions by various glycosylases is an apurinic/apyrimidinic site (AP site). The presence of an AP site within clustered DNA damage, induced following exposure to ionizing radiation or radiomimetic anticancer agents, may present a challenge to the repair machinery of thecell, if the major human AP endonuclease, HAP1, does not efficiently incise the AP site. In this study, specific oligonucleotide constructs containing an AP site located at several positions opposite to another damage [5,6-dihydrothymine (DHT), 8-oxoG, AP site, or various types of single strand breaks] on the complementary strand were used to determine the relative efficiency of the purified HAP1 protein in incising an AP site(s) from clustered DN damage. A base damage (DHT and 8-oxoG) on the opposite strand has little or no influence on the rate of incision of an AP site by HAP1. In contrast, the presence of either a second AP site, has a strong inhibitory effect on the efficiency of incision of an AP site. The eficiency of binding of HAP1 to an AP site is reduced by approx 1 order of magnitude if a single strand break (SSB) is located one or three bases 3' to the site opposite to the AP site on the complementary strand. If the AP site and either a SSB or a second AP site are located at any of the other postions relative to each other, a double strand break may result.
机译：由电离辐射诱导并在通过各种糖基化酶去除氧化碱基损伤后形成的主要DNA损伤是一个嘌呤/嘧啶二酸位点（AP位点）。如果主要的人类AP内切核酸酶HAP1无法有效地切割AP位点，则在簇状DNA损伤中（暴露于电离辐射或放射模拟抗癌剂后诱导）AP位点的存在可能对细胞的修复机制提出挑战。在这项研究中，使用了特定的寡核苷酸构建体，该构建体包含一个位于互补链上与另一个损伤[5,6-二氢胸腺嘧啶（DHT），8-oxoG，AP站点或各种类型的单链断裂]相反的几个位置的AP站点。以确定纯化的HAP1蛋白在从簇状DN损伤中切开AP位点的相对效率。相对链上的基础损伤（DHT和8-oxoG）对HAP1切割AP部位的速率几乎没有影响。相反，第二个AP位点的存在对AP位点切开效率具有强烈的抑制作用。如果单链断裂（SSB）位于互补链上与AP位点相反的位点一个3个碱基或3'个碱基，则HAP1与AP位点的结合效率会降低大约1个数量级。如果AP站点和SSB或第二AP站点位于彼此相对的任何其他位置，则可能导致双链断裂。

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