文章：

DNA拓扑异构酶II及其日益增长的生物学功能

DNA topoisomerase II and its growing repertoire of biological functions

原文发布日期：2009-04-20

DOI: 10.1038/nrc2608

类型: Review Article

开放获取: 否

要点：

1. Type II topoisomerases change DNA topology by generating transient DNA double strand breaks and are essential for all eukaryotic cells.
2. Mammalian cells have two topoisomerase II (TOP2) isoforms, TOP2α and TOP2β. TOP2α is essential for all cells, and is essential for separating replicated chromosomes. TOP2β is required for normal development, but is dispensable in some cell types. Type II topoisomerases are required for other processes such as transcription, and the precise roles of the two isoforms in these processes are a subject of current studies.
3. Type II topoisomerases use a two gate mechanism for carrying out topological changes in DNA. The enzyme requires ATP hydrolysis for its reaction. ATP hydrolysis is used for for conformational changes of the enzyme, and is not directly involved in DNA breakage or resealing.
4. Crystal structures of several domains of yeast Top2 have provided additional information about how the enzyme carries out its reactions. A recent structure of the breakage reunion domain of yeast Top2 bound to DNA has shown that the enzyme induces a large bend in the DNA that is cleaved by the enzyme.
5. Biological functions of TOP2 isoforms are modulated by a variety of protein–protein interactions. Some of these interactions may affect enzyme activity, stability and localization.
6. TOP2 activity is also modulated by post-translational modification. In addition to phosphorylation, a crucial post-translational modification of TOP2 is sumoylation. Failure to sumoylate TOP2α or to remove the SUMO modification disrupts the ability of TOP2α to separate replicated chromosomes.
7. TOP2β has a key role in the survival of some neural cells. TOP2β is important in transcriptional regulation, and it is likely that TOP2β enzyme activity is specifically required.
8. Some aspects of TOP2 function during the cell cycle are monitored by checkpoints. It has been hypothesized that a major role of checkpoints is to monitor the completion of decatenation. If so, then TOP2-dependent checkpoints may be crucial for normal chromosome segregation and genome stability.

要点翻译：

1. II型拓扑异构酶通过产生瞬时DNA双链断裂来改变DNA拓扑结构，对所有真核细胞至关重要。
2. 哺乳动物细胞拥有两种拓扑异构酶II（TOP2）亚型：TOP2α和TOP2β。TOP2α对所有细胞都不可或缺，尤其在复制染色体分离过程中起关键作用。TOP2β是正常发育所必需的，但在某些细胞类型中并非必需。II型拓扑异构酶还参与转录等其他生物学过程，这两种亚型在这些过程中的具体作用仍是当前研究的重点。
3. II型拓扑异构酶采用双闸门机制实现DNA拓扑结构改变。该酶的反应需要ATP水解供能，水解产生的能量用于驱动酶构象变化，并不直接参与DNA断裂或重接过程。
4. 酵母Top2多个结构域的晶体结构为了解该酶的反应机制提供了新见解。最近解析的酵母Top2断裂复合结构域与DNA结合的结构显示，该酶会在被切割的DNA中诱导产生大幅弯曲。
5. TOP2亚型的生物学功能通过多种蛋白质-蛋白质相互作用进行调控。部分相互作用可能影响酶活性、稳定性及细胞定位。
6. TOP2活性还受到翻译后修饰的调节。除磷酸化外，SUMO化修饰是TOP2至关重要的翻译后修饰。若TOP2α无法完成SUMO化修饰或去除SUMO修饰，将破坏其分离复制染色体的能力。
7. TOP2β在某些神经细胞的存活中发挥关键作用。该亚型在转录调控中尤为重要，很可能需要其特定的酶活性参与。
8. 细胞周期中TOP2功能的某些方面会受到检查点监控。有假说认为检查点的主要作用是监控解连环作用的完成情况。若该假说成立，则依赖于TOP2的检查点可能对正常染色体分离和基因组稳定性至关重要。

英文摘要：

DNA topoisomerases are enzymes that disentangle the topological problems that arise in double-stranded DNA. Many of these can be solved by the generation of either single or double strand breaks. However, where there is a clear requirement to alter DNA topology by introducing transient double strand breaks, only DNA topoisomerase II (TOP2) can carry out this reaction. Extensive biochemical and structural studies have provided detailed models of how TOP2 alters DNA structure, and recent molecular studies have greatly expanded knowledge of the biological contexts in which TOP2 functions, such as DNA replication, transcription and chromosome segregation — processes that are essential for preventing tumorigenesis.

摘要翻译： 

DNA拓扑异构酶是一类能够解决双链DNA中拓扑问题的酶。其中许多问题可以通过产生单链或双链断裂来解决。然而，在需要通过引入瞬时双链断裂来改变DNA拓扑结构的明确情况下，只有DNA拓扑异构酶II（TOP2）能够执行这一反应。广泛的生化和结构研究提供了TOP2如何改变DNA结构的详细模型，而最近的分子研究极大地扩展了我们对TOP2功能生物学背景的了解，例如DNA复制、转录和染色体分离——这些过程对于预防肿瘤发生至关重要。

原文链接：

DNA topoisomerase II and its growing repertoire of biological functions