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Updated: Jan 19, 2026

Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins
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A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1

Xiao-Feng Zheng1, Sanket S Acharya1, Katherine N Choe1

  • 1Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.

Nature Communications
|September 20, 2019
PubMed

Insights

Cyclin-dependent kinase 5 (CDK5) regulates the DNA damage response (DDR) by controlling the dephosphorylation of 53BP1. This finding clarifies how cells restore genome integrity after mitosis by managing 53BP1 localization.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Mitotic cells suppress the DNA damage response (DDR) by phosphorylating 53BP1, preventing its chromatin localization.
  • Proper 53BP1 dephosphorylation is crucial for genome integrity, as its premature recruitment to DNA lesions compromises mitotic fidelity.
  • Protein phosphatase 4 (PP4) dephosphorylates 53BP1 in late mitosis, enabling its G1-phase recruitment to DNA lesions.

Purpose of the Study:

  • To elucidate the mechanism controlling 53BP1 dephosphorylation kinetics during mitosis.
  • To identify the kinase responsible for regulating PP4 activity towards 53BP1.

Main Methods:

  • Investigated the role of CDK5 in mitotic cells using specific inhibitors.
  • Analyzed the phosphorylation status of PP4R3β and its interaction with 53BP1.
  • Assessed the localization of 53BP1 to damaged chromatin following CDK5 inhibition.

Main Results:

  • CDK5 is active in late mitosis in non-neuronal cells and phosphorylates PP4R3β, the regulatory subunit that binds 53BP1.
  • Inhibition of CDK5 during mitosis prevents PP4R3β phosphorylation, disrupting 53BP1 recognition and dephosphorylation by PP4.
  • This disruption prevents 53BP1 localization to damaged chromatin, highlighting CDK5's role in restoring DDR.

Conclusions:

  • CDK5 acts as a key regulator of 53BP1 recruitment by modulating PP4 activity.
  • The study reveals a novel role for CDK5 in managing the DNA damage response during the cell cycle.
  • Understanding this mechanism is critical for maintaining genome integrity and preventing mitotic errors.

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