APE1: A skilled nucleic acid surgeon.
APE1: A skilled nucleic acid surgeon.
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APE1：熟练的核酸外科医生。
DOI：
10.1016/j.dnarep.2018.08.012
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发表时间：
2018-11
期刊：
影响因子：
3.8
通讯作者：
Freudenthal BD
中科院分区：
文献类型：
--
作者：
Whitaker AM;Freudenthal BD
APE 1具有多种核酸切割活性和底物。APE 1翻转AP位点进入其紧凑的蛋白活性位点进行切割。APE 1利用螺旋内的DNA空间来去除错配和DNA损伤。APE 1用来切割其他已知底物的机制仍然是个谜。在一个有害的DNA损伤可以被其未受损的对应物取代之前，必须首先从基因组中去除损伤。这种去除和替换DNA损伤的过程是通过DNA修复过程中几种蛋白质因子的仔细协调来完成的。一种这样的因子是多功能酶人脱嘌呤/脱嘧啶核酸内切酶1（APE 1），其在碱基切除修复（BER）期间在AP位点处的DNA骨架切割活性是最为人所知的。APE 1以外科手术的精确度和技巧进行AP位点切割，通过雕刻DNA将切割位点置于其紧凑的蛋白质活性位点内的亲核攻击的最佳位置。然而，APE 1已经证明了广泛的外科专业知识，并将其DNA切割活性应用于多种DNA和RNA底物。在这里，我们讨论什么是已知的和未知的APE 1切割机制，侧重于结构和机制的考虑。重要的是，与APE 1相关的生物学功能的破坏与许多人类疾病有关，包括癌症和神经退行性疾病。APE 1机制的持续阐明对于合理的药物设计是必需的，这些药物设计旨在以新的和战略性的方式靶向其相关的修复途径。
APE1 has numerous nucleic acid cleavage activities and substrates. APE1 flips AP sites into its compact protein active site for cleavage. APE1 utilizes the intra-helical DNA space to remove mismatches and DNA damage. The mechanism used by APE1 to cleave other known substrates remains enigmatic. Before a deleterious DNA lesion can be replaced with its undamaged counterpart, the lesion must first be removed from the genome. This process of removing and replacing DNA lesions is accomplished by the careful coordination of several protein factors during DNA repair. One such factor is the multifunctional enzyme human apurinic/apyrimidinic endonuclease 1 (APE1), known best for its DNA backbone cleavage activity at AP sites during base excision repair (BER). APE1 preforms AP site incision with surgical precision and skill, by sculpting the DNA to place the cleavage site in an optimal position for nucleophilic attack within its compact protein active site. APE1, however, has demonstrated broad surgical expertise, and applies its DNA cleavage activity to a wide variety of DNA and RNA substrates. Here, we discuss what is known and unknown about APE1 cleavage mechanisms, focusing on structural and mechanistic considerations. Importantly, disruptions in the biological functions associated with APE1 are linked to numerous human maladies, including cancer and neurodegenerative diseases. The continued elucidation of APE1 mechanisms is required for rational drug design towards novel and strategic ways to target its associated repair pathways.
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