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Updated: Aug 14, 2025

Author Spotlight: Advanced Single-Molecule Techniques for Investigating Telomeric Protein-DNA Interactions
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Author Spotlight: Advanced Single-Molecule Techniques for Investigating Telomeric Protein-DNA Interactions

Published on: August 30, 2024

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Phosphorylation of TRF2 promotes its interaction with TIN2 and regulates DNA damage response at telomeres

Radka Storchova1, Matous Palek1, Natalie Palkova1

  • 1Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague CZ-14220, Czech Republic.

Nucleic Acids Research
|January 18, 2023
PubMed

Insights

Protein phosphatase magnesium-dependent 1 delta (PPM1D) interacts with the shelterin complex at telomeres. PPM1D regulates DNA repair by controlling TRF2 phosphorylation, impacting telomere stability.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Protein phosphatase magnesium-dependent 1 delta (PPM1D) is a key regulator of cell cycle checkpoints and DNA damage response.
  • The shelterin complex protects telomeres, essential for genomic stability.
  • Understanding PPM1D's role at telomeres is crucial for cancer research.

Purpose of the Study:

  • To investigate the novel interaction between PPM1D and the shelterin complex.
  • To elucidate PPM1D's function in telomere maintenance and DNA repair.

Main Methods:

  • Proximity biotinylation followed by proteomic analysis to identify protein interactions.
  • Confocal microscopy to determine subcellular localization of PPM1D.
  • In vitro and in vivo assays to study protein phosphorylation and complex formation.

Main Results:

  • PPM1D was identified as a novel interactor of the shelterin complex and localized to telomeres.
  • PPM1D inhibition or loss increased ATR-mediated phosphorylation of TRF2 at S410.
  • TRF2 phosphorylation enhanced its interaction with TIN2, while PPM1D expression impaired TIN2 and TPP1 telomeric localization.
  • PPM1D inhibition reduced 53BP1 recruitment to telomeric breaks, which was rescued by a TRF2 phosphorylation-resistant mutant.

Conclusions:

  • PPM1D plays a critical role in regulating DNA repair at telomeres.
  • TRF2 phosphorylation, modulated by PPM1D, is a key mechanism controlling shelterin complex integrity and DNA repair factor recruitment.

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