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DNA damage-induced allosteric activation of protein phosphatase PP1:NIPP1 through Src kinase-induced circularization

Dan Wu1, Gerd Van der Hoeven1, Zander Claes1

  • 1Laboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of Leuven, Belgium.

The FEBS Journal
|February 2, 2024
PubMed

Insights

DNA damage activates the protein phosphatase-1 (PP1): nuclear inhibitor of PP1 (NIPP1) complex hours later. This activation, driven by NIPP1 phosphorylation, is crucial for timely DNA repair recovery.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Protein phosphatase-1 (PP1) and its inhibitor NIPP1 form a complex that regulates DNA repair by dephosphorylating specific substrates.
  • The PP1:NIPP1 holoenzyme is inactive under normal conditions, suggesting a DNA damage-induced activation mechanism.

Purpose of the Study:

  • To elucidate the mechanism by which the PP1:NIPP1 complex is activated in response to DNA damage.
  • To investigate the role of NIPP1 phosphorylation in regulating PP1:NIPP1 activity and DNA repair.

Main Methods:

  • Investigated DNA damage-induced activation of PP1:NIPP1.
  • Utilized Src-family kinase for NIPP1 phosphorylation at tyrosine 335 (Y335).
  • Employed phospho-mimicking NIPP1 mutant (Y335E) to study constitutive activation.

Main Results:

  • DNA damage triggers PP1:NIPP1 activation after a several-hour delay via NIPP1 phosphorylation at Y335 by a Src-family kinase.
  • Activation involves dissociation of NIPP1's C terminus from PP1's active site and enhanced substrate recruitment.
  • Constitutive PP1:NIPP1 activation leads to hypo-phosphorylation of substrates and accumulation of DNA double-strand breaks.

Conclusions:

  • PP1:NIPP1 activation, mediated by NIPP1 circularization, is a delayed response to DNA damage.
  • This activation mechanism is essential for the timely recovery from DNA damage repair.
Keywords:
DNA damageNIPP1PP1Src‐family kinasesprotein dephosphorylation

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