Topoisomerase I in Human Disease Pathogenesis and Treatments.
Topoisomerase I in Human Disease Pathogenesis and Treatments.
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人类疾病发病机理和治疗中的拓扑异构酶I。
DOI：
10.1016/j.gpb.2016.02.004
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Liu Y
中科院分区：
文献类型：
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作者：
Li M;Liu Y
哺乳动物拓扑异构酶1（TOP1）是一种重要的酶，对正常发育至关重要。TOP1松弛超螺旋DNA以去除螺旋约束，否则会阻碍DNA复制和转录，从而阻止细胞生长。不幸的是，这种确切的活性可以共价捕获DNA上的TOP 1，这可能导致细胞死亡或诱变，这是肿瘤发生的前体。因此，对于细胞来说，重要的是在利用TOP 1催化活性来维持DNA拓扑结构与由于TOP 1捕获而积累毒性DNA损伤的风险之间找到适当的平衡，所述毒性DNA损伤阻止正常细胞生长。与TOP 1活性对基因组稳定性的负面属性明显矛盾的是，TOP 1诱导的DNA损伤对细胞存活的有害影响使这种酶成为癌症治疗的主要靶点，以杀死快速生长的癌细胞。此外，累积的证据支持TOP1在促进转录进展中的直接作用，而不依赖于其拓扑异构酶活性。TOP1参与转录调控最近已成为开发自闭症谱系障碍亚型潜在新疗法的焦点。显然，TOP1对人类健康的影响是多方面的。在这篇综述中，我们将总结我们目前对TOP1如何促进人类疾病以及其活性如何用于疾病治疗的理解。
Mammalian topoisomerase 1 (TOP1) is an essential enzyme for normal development. TOP1 relaxes supercoiled DNA to remove helical constraints that can otherwise hinder DNA replication and transcription and thus block cell growth. Unfortunately, this exact activity can covalently trap TOP1 on the DNA that could lead to cell death or mutagenesis, a precursor for tumorigenesis. It is therefore important for cells to find a proper balance between the utilization of the TOP1 catalytic activity to maintain DNA topology and the risk of accumulating the toxic DNA damages due to TOP1 trapping that prevents normal cell growth. In an apparent contradiction to the negative attribute of the TOP1 activity to genome stability, the detrimental effect of the TOP1-induced DNA lesions on cell survival has made this enzyme a prime target for cancer therapies to kill fast-growing cancer cells. In addition, cumulative evidence supports a direct role of TOP1 in promoting transcriptional progression independent of its topoisomerase activity. The involvement of TOP1 in transcriptional regulation has recently become a focus in developing potential new treatments for a subtype of autism spectrum disorders. Clearly, the impact of TOP1 on human health is multifold. In this review, we will summarize our current understandings on how TOP1 contributes to human diseases and how its activity is targeted for disease treatments.