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The p97-Ufd1-Npl4 ATPase complex ensures robustness of the G2/M checkpoint by facilitating CDC25A degradation

Anne Riemer1, Grzegorz Dobrynin1, Alina Dressler1

  • 1Centre for Medical Biotechnology; Faculty of Biology; University of Duisburg - Essen; Essen, Germany.

Cell Cycle (Georgetown, Tex.)
|January 17, 2014
PubMed

Insights

The p97-Ufd1-Npl4 ATPase complex directly regulates the G2/M checkpoint by promoting CDC25A degradation after DNA damage. Its inactivation causes checkpoint failure and chromosome instability.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of DNA repair
  • Chromosome segregation

Background:

  • The p97-Ufd1-Npl4 ATPase complex is known to be involved in DNA damage response and replication stress.
  • The precise mechanisms by which its inactivation leads to chromosome instability remain incompletely understood.

Purpose of the Study:

  • To elucidate the direct role of the p97-Ufd1-Npl4 complex in the G2/M checkpoint.
  • To investigate how this complex influences the response to DNA damage and prevents chromosome instability.

Main Methods:

  • Investigated the interaction of p97-Ufd1-Npl4 with CDC25A following DNA damage.
  • Utilized depletion studies to assess the impact on G2/M checkpoint function and chromosome segregation.
  • Analyzed the role of SCF-βTrCP ligase in CDC25A ubiquitination and subsequent degradation.

Main Results:

  • Demonstrated that p97-Ufd1-Npl4 directly binds to CDC25A after its ubiquitination by SCF-βTrCP.
  • Showed that p97-Ufd1-Npl4 facilitates the proteasomal degradation of CDC25A.
  • Found that depletion of Ufd1-Npl4 results in persistent CDC25A activity, leading to G2/M checkpoint failure.
  • Observed the propagation of DNA damage into mitosis, causing errors in chromosome segregation.

Conclusions:

  • The p97-Ufd1-Npl4 complex plays a critical, direct role in G2/M checkpoint signaling.
  • This complex is essential for suppressing chromosome instability by ensuring proper cell cycle progression after DNA damage.
  • The findings reveal a novel mechanism by which p97-Ufd1-Npl4 maintains genomic integrity.
Keywords:
DNA damagecheckpointchromosome instabilitydegradationubiquitin

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