XRCC1 interactions with multiple DNA glycosylases: A model for its recruitment to base excision repair
XRCC1 interactions with multiple DNA glycosylases: A model for its recruitment to base excision repair
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DOI：
10.1016/j.dnarep.2005.04.014
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发表时间：
2005-07-12
期刊：
影响因子：
3.8
通讯作者：
Radicella, JP
中科院分区：
文献类型：
--
作者：
Campalans, A;Marsin, S;Radicella, JP
DNA中化学修饰的碱基的修复是通过碱基切除修复(BER)完成的。这一途径是由一种特定的DNA糖基酶启动的，该酶识别并切除改变的碱基以产生碱性(AP)位点。在APEI切割AP位点后，修复通过重新合成和连接步骤进行。在哺乳动物细胞中，XRCC1蛋白。XRCC1是维持基因组稳定性所必需的，参与碱基切除和单链断裂修复，通过与人DNA糖基酶hOGG1和NEIL1相互作用参与BER的第一步。为了分析XRCC1与DNA糖基酶相互作用的一般机制的可能性，我们使用XRCC1从人细胞提取液中下调DNA糖基酶活性。XRCC1具有DNA糖基酶活性，除8-氧鸟嘌呤外，还能去除次黄嘌呤和二氢胸腺嘧啶，但不能去除尿嘧啶，与纯化蛋白的生化分析证实了XRCC1与MPG、hNTH1或hNEIL2之间的相互作用。此外，XRCC1还能刺激这些酶的活性。体内定位研究表明，经过基因毒性处理后，这些DNA糖基酶可以被发现与XRCC1病灶相关。我们的结果支持BER模型，在该模型中，XRCC1通过识别损伤的酶被招募到烷基化或氧化的碱基的修复中。然后，XRCC1将协调随后的酶步骤并调节所有涉及的蛋白质的活性，(C)2005 Elsevier B.V.保留所有紧身衣。
Repair of chemically modified bases in DNA is accomplished through base excision repair (BER). This pathway is initiated by a specific DNA glycosylase that recognizes and excises the altered base to yield an abasic (AP) site. After cleavage of the AP site by APEI, repair proceeds through re-synthesis and ligation steps. In mammalian cells, the XRCC1 protein. essential for the maintenance of genomic stability, is involved in both base excision and single-strand break repair, XRCC1 participates in the first step of BER by interacting with the human DNA glycosylases hOGG1 and NEIL1. To analyze the possibility of a general mechanism involving the interaction of XRCC1 with DNA glycosylases we used XRCC1 to pull-down DNA glycosylases activities from human cell extracts. XRCC1 co-purities with DNA glycosylase activities capable of excising hypoxanthine and dihydrothymine, in addition to 8-oxoguanine, but not uracil, Biochemical analyses with the purified proteins confirmed the interactions between XRCC1 and MPG, hNTH1 or hNEIL2. Furthermore, XRCC1 stimulates the activities of these enzymes. In vivo localization studies show that after genotoxic treatments these DNA glycosylases can be found associated with XRCC1 foci. Our results support a BER model in which XRCC1 is recruited to the repair of alkylated or oxidized bases by the enzyme recognizing the lesion. XRCC1 would then coordinate the subsequent enzymatic steps and modulate the activities of all the proteins involved, (c) 2005 Elsevier B.V. All tights reserved.