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Updated: Mar 17, 2026

Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins
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53BP1 and USP28 mediate p53 activation and G1 arrest after centrosome loss or extended mitotic duration

Franz Meitinger1, John V Anzola2, Manuel Kaulich3

  • 1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093 Ludwig Institute for Cancer Research, La Jolla, CA 92093.

The Journal of Cell Biology
|July 20, 2016
PubMed

Insights

Centrosome loss triggers cell cycle arrest via a mechanism involving 53BP1 and USP28, which communicate mitotic issues to the p53 pathway. TRIM37 enforces single centrosome assembly, preventing mitotic defects.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Centrosome loss in human cells induces p53-dependent G1 arrest through an unidentified mechanism.
  • Centrosome duplication inhibitors like centrinone are crucial tools for studying cell cycle regulation.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying p53-dependent G1 arrest following centrosome loss.
  • To identify key regulators involved in sensing centrosome loss and communicating this to the p53 pathway.

Main Methods:

  • Genome-wide CRISPR/Cas9 screening was employed to identify centrinone resistance genes.
  • Gene deletion studies (TP53BP1, USP28, TRIM37) were performed to assess their roles in cell cycle arrest and proliferation.
  • Analysis of p53 elevation, mitotic defects, and centrosome assembly was conducted in knockout cell lines.

Main Results:

  • The screen identified 53BP1, USP28, and TRIM37 as critical for the response to centrosome loss.
  • Deletion of TP53BP1 or USP28 prevented p53 elevation upon centrosome loss but did not affect arrest induced by other stresses.
  • TRIM37 knockout cells exhibited suppressed mitotic defects and formed ectopic centrosomal foci, while TP53BP1 and USP28 knockouts showed impaired proliferation.

Conclusions:

  • A 53BP1-USP28 module is essential for transmitting mitotic challenges to the p53 pathway.
  • TRIM37 acts as a crucial factor in maintaining the singularity of centrosome assembly.
  • Understanding these pathways offers insights into cell cycle control and potential therapeutic targets.

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