Reciprocal Regulation between 53BP1 and the Anaphase-Promoting Complex/Cyclosome Is Required for Genomic Stability during Mitotic Stress

Publication date: 21 February 2017
Source:Cell Reports, Volume 18, Issue 8
Author(s): Thomas J. Kucharski, Paul E. Minshall, Mohamed Moustafa-Kamal, Andrew S. Turnell, Jose G. Teodoro
The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets substrates for degradation to promote mitotic progression. Here, we show that the DNA damage response protein 53BP1 contains conserved KEN boxes that are required for APC/C-dependent degradation in early mitosis. Mutation of the 53BP1 KEN boxes stabilized the protein and extended mitotic duration, whereas 53BP1 knockdown resulted in a shorter and delayed mitosis. Loss of 53BP1 increased APC/C activity, and we show that 53BP1 is a direct APC/C inhibitor. Although 53BP1 function is not absolutely required for normal cell cycle progression, knockdown was highly toxic in combination with mitotic spindle poisons. Moreover, chemical inhibition of the APC/C was able to rescue the lethality of 53BP1 loss. Our findings reveal a reciprocal regulation between 53BP1 and APC/C that is required for response to mitotic stress and may contribute to the tumor-suppressor functions of 53BP1.

Graphical abstract

Teaser

Kucharski et al. find that 53BP1 is a mitotic APC/C substrate and an interphase inhibitor. 53BP1 silencing leads to a hyperactive APC/C, resulting in cell cycle defects and sensitivity to mitotic poisons. This helps to explain observations that 53BP1 null mice display aneuploidy and cancer susceptibility.


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