Aprataxin, poly-ADP ribose polymerase 1 (PARP-1) and apurinic endonuclease 1 (APE1) function together to protect the genome against oxidative damage
Aprataxin, poly-ADP ribose polymerase 1 (PARP-1) and apurinic endonuclease 1 (APE1) function together to protect the genome against oxidative damage
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DOI：
10.1093/hmg/ddp359
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发表时间：
2009-11-01
影响因子：
3.5
通讯作者：
Lavin, Martin F.
中科院分区：
文献类型：
--
作者：
Harris, Janelle L.;Jakob, Burkhard;Lavin, Martin F.
Aprataxin是一种DNA修复蛋白，在神经退行性疾病共济失调眼动型失用1型(AOA1)中存在缺陷，它处理流产连接的产物5‘端腺化DNA。除了与单链断裂修复蛋白XRCC1相互作用外，aprataxin还与多聚ADP核糖聚合酶1(PARP-1)相互作用，PARP-1是检测DNA单链断裂的关键角色。在这里，我们揭示了AOA1细胞中PARP-1、无嘌呤核酸内切酶1(APE1)和OGG1的表达减少，并证明了PARP-1在DNA断裂部位募集aprataxin所必需的。虽然抑制PARP活性在体外不影响aprataxin的活性，但它在体内延缓了其在DNA损伤部位的募集。我们还证明了AOA1细胞中氧化DNA损伤水平的升高，以及碱基切除和缺口填充修复效率的降低，表明aprataxin、PARP-1、APE-1和OGG1在DNA损伤反应中具有协同作用。这些数据支持APRATAIN对碱基切除修复的直接和间接调节作用。
Aprataxin, defective in the neurodegenerative disorder ataxia oculomotor apraxia type 1 (AOA1), is a DNA repair protein that processes the product of abortive ligations, 5' adenylated DNA. In addition to its interaction with the single-strand break repair protein XRCC1, aprataxin also interacts with poly-ADP ribose polymerase 1 (PARP-1), a key player in the detection of DNA single-strand breaks. Here, we reveal reduced expression of PARP-1, apurinic endonuclease 1 (APE1) and OGG1 in AOA1 cells and demonstrate a requirement for PARP-1 in the recruitment of aprataxin to sites of DNA breaks. While inhibition of PARP activity did not affect aprataxin activity in vitro, it retarded its recruitment to sites of DNA damage in vivo. We also demonstrate the presence of elevated levels of oxidative DNA damage in AOA1 cells coupled with reduced base excision and gap filling repair efficiencies indicative of a synergy between aprataxin, PARP-1, APE-1 and OGG1 in the DNA damage response. These data support both direct and indirect modulating functions for aprataxin on base excision repair.