Redox regulation of the DNA repair function of the human AP endonuclease Ape1/ref-1
Redox regulation of the DNA repair function of the human AP endonuclease Ape1/ref-1
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DOI：
10.1089/15230860152543014
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发表时间：
2001-08-01
影响因子：
6.6
通讯作者：
Parsons, SH
中科院分区：
文献类型：
--
作者：
Kelley, MR;Parsons, SH
DNA碱基切除修复(BER)途径中的第二种酶，脱嘌呤/脱嘧啶(AP)内切酶或APE1，立即将磷酸二酯骨架5‘端水解到AP位点，产生正常的3’-羟基和碱性脱氧核糖-5-磷酸，该酶由BER途径的后续酶处理。AP位点是最常见的DNA损伤形式，AP位点在DNA中的持续存在会导致DNA复制受阻、细胞毒性突变和遗传不稳定。有趣的是，Apel/REF-1是一种多功能蛋白，它不仅是一种DNA修复酶，还可以作为氧化还原因子，维持转录因子Fos、Jun、核因子-kappaB、PAX(成对盒基因家族)、低氧诱导因子-1α(HIF-1α)、HIF-1样因子和P53处于活跃的还原状态。APEL/REF-1还参与了许多其他活动，其中之一是激活需要还原才能发挥活性的生物还原药物。在这份报告中，我们提供了支持我们的发现的数据，即Apel/REF-1的另一个明显影响AP内切酶活性的翻译后修饰是该蛋白的还原或氧化。此外，我们的数据表明，参与这种氧化还原调节的至少一个位点是位于310位的半胱氨酸氨基酸，紧邻DNA修复活性位点309位的关键组氨酸残基。这些发现表明，Apel/REF-1蛋白在翻译后水平上可能比最初想象的更密切地受到调控。
The second enzyme in the DNA base excision repair (BER) pathway, apurinic/apyrimidinic (AP) endonuclease or Ape1, hydrolyzes the phosphodiester backbone immediately 5' to an AP site generating a normal 3'-hydroxyl group and an abasic deoxyribose-5-phosphate, which is processed by subsequent enzymes of the BER pathway. AP sites are the most common form of DNA damage, and the persistence of AP sites in DNA results in a block to DNA replication, cytotoxic mutations, and genetic instability. Interestingly, Apel/ref-1 is a multifunctional protein that not only is a DNA repair enzyme, but also functions as a redox factor maintaining transcription factors, such as Fos, Jun, nuclear factor-kappaB, PAX (paired box-containing family of genes), hypoxia inducible factor-la (HIF-1alpha), HIF-1-like factor, and p53, in an active reduced state. Apel/ref-1 has also been implicated in a number of other activities, one of which is the activation of bioreductive drugs requiring reduction for activity. In this report, we present data supporting our findings that another level of posttranslational modification of Apel/ref-1 that clearly affects the AP endonuclease activity is the reduction or oxidation of this protein. Furthermore, we show data demonstrating that at least one of the sites involved in this redox regulation is the cysteine amino acid found at position 310, immediately adjacent to the crucial histidine residue at position 309 in the DNA repair active site. These findings suggest that the Apel/ref-1 protein may be much more intimately regulated at the posttranslational level than initially imagined.