Reciprocal regulation between 53BP1 and the anaphase-promoting complex/cyclosome is required for genomic stability during mitotic stress

Research output: Contribution to journalArticlepeer-review

Authors

  • Thomas J Kucharski
  • Paul Minshall
  • Mohamed Moustafa-Kamal
  • Andrew Turnell
  • Jose Teodoro

Colleges, School and Institutes

External organisations

  • McGill University

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.

Details

Original languageEnglish
Pages (from-to)1982-1995
Number of pages14
JournalCell Reports
Volume18
Issue number8
Publication statusPublished - 21 Feb 2017

Keywords

  • Mitosis, apc/c, 53BP1, genome stability