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Cell Rep. 2017 Feb 21;18(8):1982-1995. doi: 10.1016/j.celrep.2017.01.080.

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

Author information

1
Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
2
School of Cancer and Genomic Sciences, College of Medical and Dental Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
3
Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; Department of Microbiology and Immunology, Montreal, QC H3A 2B4, Canada. Electronic address: jose.teodoro@mcgill.ca.

Abstract

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.

KEYWORDS:

53BP1; anaphase-promoting complex/cyclosome; mitosis; spindle poison; ubiquitin

PMID:
28228263
DOI:
10.1016/j.celrep.2017.01.080
[Indexed for MEDLINE]
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