Damaged DNA-binding Protein 1 (DDB1) Interacts with Cdh1 and Modulates the Function of APC/CCdh1

Xiao-Bin Lv,Fangyun Xie,Kaishun Hu,Yuanzhong Wu,Lin-Lin Cao,Xia Han,Yi Sang,Yi-Xin Zeng,Tiebang Kang

doi:10.1074/jbc.m109.094144

Xiao-Bin Lv, Fangyun Xie + Show 7 more

Open Access

https://doi.org/10.1074/jbc.m109.094144

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Abstract

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.

Highlights

Repeats form a seven-blade propeller structure that mediates protein-protein interactions
As an E3 ligase capable of degrading cyclin E, p27, and Cdt1, Damaged DNA-binding protein 1 (DDB1) plays a key role in the normal cell cycle and in response to DNA damage (14 – 19)
Cells depleted of DDB1 were much the Cul4-DDB1-DCAF ubiquitin E3 ligase with Cul4 [23]. slower to exit from M phase than those depleted of Cdh1, indicating that modulation of APC/CCdh1 activity by Cdh1 binding only partially accounts for the delayed mitotic exit in cells depleted of DDB1

Summary

Introduction

Repeats form a seven-blade propeller structure that mediates protein-protein interactions. We report that DDB1 may have a novel role, independent of the Cul4-DDB1 complex, in normal mitotic exit, at least partially by regulating APC/CCdh1 activity.

Results

Conclusion