Tyrosyl-DNA phosphodiesterase as a target for anticancer therapy
Tyrosyl-DNA phosphodiesterase as a target for anticancer therapy
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DOI：
10.2174/187152008784220357
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发表时间：
2008-05-01
影响因子：
2.8
通讯作者：
Pommier, Yves
中科院分区：
文献类型：
--
作者：
Dexheimer, Thomas S.;Antony, Smitha;Pommier, Yves
酪氨酰-DNA磷酸二酯酶1（Tdp 1）是最近发现的催化3 '-磷酸酪氨酰键水解的酶。这种连接在拓扑异构酶I（Top1）的DNA加工活性之后在体内形成。由于这个原因，Tdp 1已被牵连在修复不可逆的Top1-DNA共价复合物，这可以产生的外源性或内源性因素。Tdp 1被认为是Top1的潜在治疗共靶点，因为它似乎抵消了Top1抑制剂如喜树碱及其临床使用的衍生物的作用。因此，通过减少Top1-DNA损伤的修复，Tdp 1抑制剂有可能增加Top1抑制剂的抗癌活性，前提是存在与DNA检查点和修复途径相关的遗传异常。人Tdp 1还可以水解其他3 '端DNA改变，包括3'-磷酸乙醇酸和3 '-脱碱基位点，表明它可能作为一般的3'-DNA磷酸二酯酶和修复酶发挥作用。Tdp 1在人类中的重要性通过观察到人类TDP 1基因中的隐性突变是导致遗传性疾病脊髓小脑共济失调伴轴突神经病（SCAN 1）的原因而突出。本文综述了Tdp 1的生物化学和细胞过程，以及开发Tdp 1抑制剂用于抗癌治疗的基本原理。
Tyrosyl-DNA phosphodiesterase 1 ( Tdp1) is a recently discovered enzyme that catalyzes the hydrolysis of 3'-phosphotyrosyl bonds. Such linkages form in vivo following the DNA processing activity of topoisomerase I (Top1). For this reason, Tdp1 has been implicated in the repair of irreversible Top1-DNA covalent complexes, which can be generated by either exogenous or endogenous factors. Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin and its clinically used derivatives. Thus, by reducing the repair of Top1-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors provided there is a presence of genetic abnormalities related to DNA checkpoint and repair pathways. Human Tdp1 can also hydrolyze other 3'-end DNA alterations including 3'-phosphoglycolates and 3'-abasic sites indicating it may function as a general 3'-DNA phosphodiesterase and repair enzyme. The importance of Tdp1 in humans is highlighted by the observation that a recessive mutation in the human TDP1 gene is responsible for the inherited disorder, spinocerebellar ataxia with axonal neuropathy ( SCAN1). This review provides a summary of the biochemical and cellular processes performed by Tdp1 as well as the rationale behind the development of Tdp1 inhibitors for anticancer therapy.