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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Genomic Instability / genetics*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mitosis / genetics*
  • Spindle Apparatus / metabolism
  • Tumor Suppressor p53-Binding Protein 1 / metabolism*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Cell Cycle Proteins
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • Anaphase-Promoting Complex-Cyclosome
  • Ubiquitin-Protein Ligases