Involvement of the DNA repair protein hHR23 in p53 degradation
Involvement of the DNA repair protein hHR23 in p53 degradation
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DOI：
10.1128/mcb.23.24.8960-8969.2003
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发表时间：
2003-12-01
影响因子：
5.3
通讯作者：
Blattner, C
中科院分区：
文献类型：
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作者：
Glockzin, S;Ogi, FX;Blattner, C
肿瘤抑制蛋白p53的稳定性通过泛素-蛋白酶体依赖性蛋白水解途径调节。与此途径的大多数底物一样，p53在蛋白酶体介导的降解之前通过连接多聚泛素链进行修饰。然而，目前尚不清楚将多聚泛素化的p53分子递送至蛋白酶体的机制。在这里，我们表明，人类DNA修复蛋白hHR 23结合到多泛素化的p53通过其羧基末端泛素相关（乌巴）域屏蔽p53从去泛素化在体外和体内。此外，通过RNA干扰下调细胞内hHR 23的表达导致p53的积累。由于HHR 23的Ubl结构域已被证明与26 S蛋白酶体相互作用，我们提出HHR 23本质上参与了将聚泛素化的p53分子递送到蛋白酶体。在该模型中，hHR 23的乌巴结构域与p53上形成的多聚泛素链结合并保护它们免于去泛素化，而Ubl结构域将多聚泛素化的p53分子递送至蛋白酶体。
The stability of the tumor suppressor protein p53 is regulated via the ubiquitin-proteasome-dependent proteolytic pathway. Like most substrates of this pathway, p53 is modified by the attachment of polyubiquitin chains prior to proteasome-mediated degradation. However, the mechanism(s) involved in the delivery of polyubiquitylated p53 molecules to the proteasome are currently unclear. Here, we show that the human DNA repair protein hHR23 binds to polyubiquitylated p53 via its carboxyl-terminal ubiquitin-associated (Uba) domain shielding p53 from deubiquitylation in vitro and in vivo. In addition, downregulation of hHR23 expression within cells by RNA interference results in accumulation of p53. Since the Ubl domain of hHR23 has been shown to interact with the 26S proteasome, we propose that hHR23 is intrinsically involved in the delivery of polyubiquitylated p53 molecules to the proteasome. In this model, the Uba domain of hHR23 binds to polyubiquitin chains formed on p53 and protects them from deubiquitylation, while the Ubl domain delivers the polyubiquitylated p53 molecules to the proteasome.