How adeno-associated virus Rep78 protein arrests cells completely in S phase
How adeno-associated virus Rep78 protein arrests cells completely in S phase
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DOI：
10.1073/pnas.0504583102
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发表时间：
2005-09-20
影响因子：
11.1
通讯作者：
Beard, P
中科院分区：
文献类型：
--
作者：
Berthet, C;Raj, K;Beard, P
腺相关病毒Rep78蛋白具有抗细胞增殖作用。它抑制细胞周期进程，特别是Rep78诱导S期内的完全停滞，这是细胞DNA损伤后罕见的反应。我们研究了Rep78如何实现如此高效的S相位块。Rep78通过一种新的方式抑制Cdc2SA活性，其中两种蛋白质之间的结合稳定了Cdc25A，从而增加了其丰度，同时阻止了其底物细胞周期蛋白依赖性激酶（Cdk）2和Cdk 1的进入。这种效应本身不会诱导完全的S期阻滞。此外，Rep78以及Rep68在细胞染色质中产生切口，诱导由共济失调毛细血管扩张突变（ATM）介导的DNA损伤反应，导致G（1）和G（2）阻滞。突变分析表明Rep78的锌指结构域和核酸酶活性都是S期阻滞所必需的。结果表明，真正的S期阻滞不能通过单一途径实现，并且腺相关病毒Rep78蛋白通过干扰通常会导致S期减慢的两条途径将细胞阻滞在S期内。
Adeno-associated virus Rep78 protein has anti proliferative effects on cells. It inhibits cell cycle progression, and, in particular, Rep78 induces a complete arrest within S phase, a response rarely seen after cell DNA damage. We examined how Rep78 achieves such an efficient S phase block. Rep78 inhibits Cdc2SA activity by a novel means in which binding between the two proteins stabilizes Cdc25A, thus increasing its abundance, while at the same time preventing access to its substrates cyclin-dependent kinase (Cdk) 2 and Cdk1. This effect alone does not induce a complete S phase block. In addition, Rep78, as well as Rep68, produces nicks in the cellular chromatin, inducing a DNA damage response mediated by ataxia telangiectasia mutated (ATM) leading to G(1) and G(2) blocks. Mutational analysis shows that the zinc finger domain and nuclease activity of Rep78 are both required for the S phase block. The results suggest that a true S phase block cannot be achieved through a single pathway, and that adeno-associated virus Rep78 protein arrests cells within S phase by interfering with two pathways that would normally lead to an S phase slow-down.