Abstract LB-98: DDB1 interacts with Cdh1 and modulates the function of APCCdh1

Control of cell cycle division by the anaphase promoting complex or cyclosome (APC/C) ubiquitin ligase depends on its coactivators, two WD40 repeat proteins, Cdc20 and Cdh1. APC/CCdh1 becomes active during mitotic exit and has essential targets in G1 phase by poorly understood mechanisms. In this report, we provide evidence that DDB1 (Damaged DNA-binding protein 1), a recently identified protein interacting with numerous proteins containing WD40 domains, is capable of binding with the WD40 domains of Cdh1, but not of Cdc20, through its BPA and BPC domains. Moreover, cells lacking DDB1 exhibit markedly elevated protein levels of the substrates for APC/CCdh1, and mitotic cells depleting DDB1 significantly delay mitotic exit, demonstrating that such an interaction between DDB1 and Cdh1 plays a critical role in regulating APC/CCdh1 activity. On the contrary, cells depleting Cdh1 have no effect on the UV-induced degradation of Cdt1, the main function of DDB1 as an E3 ligase. Strikingly, the APCCdh1 substrates are normal in the cells knock-down of Cul4A and CulB, which along with DDB1 forms an E3 ligase complex, indicating that DDB1 modulates the function of APCCdh1 in a manner independent on the Cul4-DDB1 complex. Taken together, DDB1 may functionally regulate the normal mitotic exit by modulating APCCdh1 activity, revealing for the first time that three E3 ligases, DDB1, Cdh1, and Skp2, may cooperate to tightly control cell cycle division. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-98.