文章：

拓扑异构酶介导的染色体断裂修复：许多游戏中的新兴参与者

Topoisomerase-mediated chromosomal break repair: an emerging player in many games

原文发布日期：2015-02-19

DOI: 10.1038/nrc3892

类型: Review Article

开放获取: 否

要点：

1. Topoisomerases are elegant biological tools that have evolved to resolve nucleic acid entanglements during replication, transcription and recombination.
2. Trapping of topoisomerases on DNA results in protein-linked DNA breaks (PDBs), which are widely exploited by topoisomerase-targeting cancer therapies.
3. PDB precision scissors (tyrosyl-DNA phosphodiesterase 1 (TDP1) and TDP2) are enzymes that are capable of liberating stalled topoisomerases from DNA termini without cleaving the DNA.
4. The inappropriate repair of PDBs can promote cancer in a tissue-specific manner — a process that is closely linked to gene transcription.
5. Transcription-associated PDBs can cause gene deletion, chromosomal rearrangement and therapy-induced secondary malignancy.

要点翻译：

1. 拓扑异构酶是精妙的生物工具，在复制、转录和重组过程中进化出解决核酸缠绕的能力。
2. 拓扑异构酶在DNA上的捕获会导致蛋白质连接的DNA断裂（PDBs），这一机制被拓扑异构酶靶向癌症疗法广泛利用。
3. PDB精密剪刀（酪氨酰-DNA磷酸二酯酶1（TDP1）和TDP2）是一类能够从DNA末端释放停滞拓扑异构酶而不切割DNA的酶。
4. PDBs的不当修复可能以组织特异性方式促进癌症——这一过程与基因转录密切相关。
5. 转录相关的PDBs可导致基因缺失、染色体重排和治疗诱发的继发性恶性肿瘤。

英文摘要：

The mammalian genome is constantly challenged by exogenous and endogenous threats. Although much is known about the mechanisms that maintain DNA and RNA integrity, we know surprisingly little about the mechanisms that underpin the pathology and tissue specificity of many disorders caused by defective responses to DNA or RNA damage. Of the different types of endogenous damage, protein-linked DNA breaks (PDBs) are emerging as an important player in cancer development and therapy. PDBs can arise during the abortive activity of DNA topoisomerases, a class of enzymes that modulate DNA topology during several chromosomal transactions, such as gene transcription and DNA replication, recombination and repair. In this Review, we discuss the mechanisms underpinning topoisomerase-induced PDB formation and repair with a focus on their role during gene transcription and the development of tissue-specific cancers.

摘要翻译： 

哺乳动物基因组持续受到外源性和内源性威胁。尽管我们对维持DNA与RNA完整性的机制已有较多了解，但对DNA或RNA损伤应答缺陷所致多种疾病的病理机制和组织特异性却知之甚少。在各种内源性损伤中，蛋白连接的DNA断裂（PDBs）正成为癌症发生与治疗的重要因素。PDBs可因DNA拓扑异构酶的中断活性而产生；这类酶在基因转录、DNA复制、重组及修复等多种染色质事务中调控DNA拓扑结构。本综述讨论拓扑异构酶诱导PDB形成与修复的机制，重点阐述其在基因转录及组织特异性癌症发展中的作用。

原文链接：

Topoisomerase-mediated chromosomal break repair: an emerging player in many games