AP endonucleases and the many functions of Ref-1
AP endonucleases and the many functions of Ref-1
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DOI：
10.1165/ajrcmb.25.6.f220
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发表时间：
2001-12-01
影响因子：
6.4
通讯作者：
Hunninghake, GW
中科院分区：
文献类型：
--
作者：
Flaherty, DM;Monick, MM;Hunninghake, GW
APE-1/Ref-1是一种普遍存在的多功能蛋白，具有DNA修复活性和氧化还原调节活性。 APE-1/Ref-1 因其核酸内切酶活性而最初被命名为无嘌呤/无嘧啶核酸内切酶 (APE-1) 和 HAP-1（人 APE-1），APE-1/Ref-1 是碱基切除修复途径中的主要酶 (1)，并参与修复细胞 DNA 的自发损伤和氧化损伤 (2)。在信号转导中，APE-1/Ref-1 对于介导许多转录因子的 DNA 结合非常重要，包括 AP-1、核因子 (NF)-B、Pax-5、Pax-8、HIF-1 和 HLF（表 1）(2-8)。尽管命名法尚未标准化，但许多作者将该蛋白称为 APE-1/Ref-1 以反映其双重功能。尽管细胞内和不同细胞类型之间存在复杂的分布模式，但 APE-1/Ref-1 普遍表达 (9–13)。这些细胞分布模式可能与 APE-1/Ref-1 的不同功能有关。基于其多种功能，APE-1/Ref-1 可能在维持基因组完整性和通过氧化还原激活多种转录因子来调节基因表达方面发挥着重要作用。 据估计，体外人类细胞会以大约 10,000 个碱基/天/细胞的速率进行 DNA 自发脱嘌呤 (14)，其中最大数量的无嘌呤/无嘧啶 (AP) 位点出现在大脑、心脏和结肠中 (15)。除了核苷酸自发丢失之外，DNA 还可能因氧化应激而受损，从而导致碱基和糖氧化 (16)。为了保护基因组的完整性，所有细胞都开发了修复系统来切除和替换DNA中受损的核苷酸（AP位点）。在碱基切除修复途径中，受损的碱基被 DNA 糖基化酶切除，形成 AP 位点。 APE-1/Ref-1 将 DNA 主链 5 切割至 AP 位点，并通过 DNA 聚合酶和 DNA 连接酶完成修复 (17–19)。核酸内切酶有两个家族，它们根据其功能以及与大肠杆菌核酸外切酶的同源性进行区分 (20)。 APE-1/Ref-1 属于 AP 核酸内切酶两个家族中的第一个，并且具有相同的序列
APE-1/Ref-1 is a ubiquitous multifunctional protein that possesses both DNA repair activity and redox regulatory activity. Originally named apurinic/apyrimidinic endonuclease (APE-1) and HAP-1 (Human APE-1) for its endonuclease activity, APE-1/Ref-1 is a major enzyme in the base excision repair pathway (1) and is involved in repair of spontaneous and oxidative damage to cellular DNA (2). In signal transduction, APE-1/Ref-1 is important in mediating DNA binding of a number of transcription factors including AP-1, nuclear factor (NF)-B, Pax-5, Pax-8, HIF-1, and HLF (Table 1)(2–8). Although the nomenclature is not standardized, many authors refer to the protein as APE-1/Ref-1 to reflect its dual function. APE-1/Ref-1 is ubiquitously expressed, though there are complex patterns of distribution within cells and between different cell types (9–13). These patterns of cellular distribution may be related to the varying functions of APE-1/Ref-1. Based on its multiple functions, APE-1/Ref-1 likely plays an important role in maintaining genomic integrity and in regulating gene expression via redox activation of a variety of transcription factors.Human cells in vitro are estimated to undergo spontaneous depurination of DNA at a rate of approximately 10,000 bases/day/cell (14), with the greatest number of apurinic/apyrimidinic (AP) sites occurring in the brain, heart, and colon (15). In addition to spontaneous loss of nucleotides, DNA can also be damaged via oxidant stress that results in oxidation of bases and sugars (16). To protect the integrity of the genome, all cells have developed a repair system to excise and replace the damaged nucleotides (AP sites) in DNA. In the base excision repair pathway, damaged bases are excised by a DNA glycosylase, creating an AP site. APE-1/Ref-1 cleaves the DNA backbone 5 to the AP site and repair is completed by DNA polymerase and DNA ligase (17–19). There are two families of endonucleases that are differentiated based on their functions and homology to Escherichia coli exonucleases (20). APE-1/Ref-1 belongs to the first of two families of AP endonucleases and shares se-