Damaged DNA-binding protein 1 (DDB1) interacts with Cdh1 and modulates the function of APC/CCdh1.
Damaged DNA-binding protein 1 (DDB1) interacts with Cdh1 and modulates the function of APC/CCdh1.
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受损的 DNA 结合蛋白 1 (DDB1) 与 Cdh1 相互作用并调节 APC/CCdh1 的功能
DOI：
10.1074/jbc.m109.094144
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发表时间：
2010-06-11
期刊：
影响因子：
--
通讯作者：
Kang T
中科院分区：
文献类型：
--
作者：
Lv XB;Xie F;Hu K;Wu Y;Cao LL;Han X;Sang Y;Zeng YX;Kang T
APC/CCDh 1在有丝分裂退出中起关键作用，并在G1期具有重要靶点;然而，这些机制知之甚少。在这份报告中，我们提供的证据表明，受损的DNA结合蛋白1（DDB 1）是能够结合的WD 40域的Cdh 1，但不是Cdc 20，通过其BPA和BPC域。此外，缺乏DDB 1的细胞表现出APC/CCDh 1蛋白底物的显著升高水平。DDB 1在有丝分裂细胞中的消耗显著延迟有丝分裂退出，这表明DDB 1和Cdh 1之间的相互作用在调节APC/CCDh 1活性中起关键作用。然而，细胞耗尽Cdh 1表现出没有变化的紫外线诱导的降解Cdt 1，DDB 1作为E3连接酶的主要功能。引人注目的是，APC/CCDh 1底物水平在Cul 4 A和Cul 4 B的细胞敲除中是正常的，Cul 4 A和Cul 4 B与DDB 1沿着形成E3连接酶复合物。这一发现表明DDB 1以不依赖于Cul 4-DDB 1复合物的方式调节APC/CCDh 1的功能。我们的研究结果表明，DDB 1可能通过调节APC/CCDh 1活性来功能性调节有丝分裂退出。本研究揭示了DDB 1、Cdh 1和Skp 2之间可能存在着相互作用，共同调控细胞周期的分裂。
APC/CCdh1 plays a key role in mitotic exit and has essential targets in the G1 phase; however, these mechanisms are poorly understood. In this report, we provide evidence that damaged DNA-binding protein 1 (DDB1) is capable of binding the WD40 domains of Cdh1, but not of Cdc20, through its BPA and BPC domains. Moreover, cells lacking DDB1 exhibit markedly elevated levels of the protein substrates of APC/CCdh1. Depletion of DDB1 in mitotic cells significantly delays mitotic exit, which demonstrates that the interaction between DDB1 and Cdh1 plays a critical role in regulating APC/CCdh1 activity. However, cells depleted of Cdh1 demonstrated no change in the UV-induced degradation of Cdt1, the main function of DDB1 as an E3 ligase. Strikingly, the APC/CCdh1 substrate levels are normal in cell knockdowns of Cul4A and Cul4B, which, along with DDB1, form an E3 ligase complex. This finding indicates that DDB1 modulates the function of APC/CCdh1 in a manner independent on the Cul4-DDB1 complex. Our results suggest that DDB1 may functionally regulate mitotic exit by modulating APC/CCdh1 activity. This study reveals that there may be cross-talk among DDB1, Cdh1, and Skp2 in the control of cell cycle division.