BIOLOGICAL FUNCTION OF MAMMALIAN TOPOISOMERASE II BETA

这个提议的主要目的是回答这个问题，为什么两种类型的DNA拓扑异构酶看似相同的酶性质都需要在哺乳动物的发育。在这一中心主题下，有三个具体目标。目的1提出了一种假设，即拓扑异构酶II α和β基因的活性是可互换的，但它们在时间和/或组织特异性调节上的差异是两者的必要性的原因。Aim II旨在回答最近发现的问题，即小鼠β亚型的失活会阻止正常的轴突生长。报告基因（GFP）将融合到拓扑异构酶II β中，以便在发育过程中对该异构体进行详细监测。最后，目的III解决了一个假设，即同种异构体的不同c端结构域是它们不可或缺的原因。这一假设将通过交换一个同工异构体的c端结构域来验证。

The main goal of this proposal is to answer the question why two typeII DNA topoisomerases with seemingly identical enzymatic properties are both needed in mammalian development. Under this central theme there are three specific aims. Aim I addresses the hypothesis that the activities are interchangeable but differences in temporal and/or tissue specific regulation of the topoisomerase II alpha and beta genes are responsible for the necessity of both. Aim II is directed at answering the question raised by the recent finding that inactivation of the beta isoform in the mouse prevents normal axon growth. A reporter gene (GFP) will be fused to topoisomerase II beta to allow detailed monitoring of this isoform during development. Finally, aim III addresses the hypothesis that the distinct C-terminal domain of the isoforms are responsible for their indispensability. This hypothesis will be tested through swapping of the C-terminal domain of one isoform by another.