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Modulation of LSD1 phosphorylation by CK2/WIP1 regulates RNF168-dependent 53BP1 recruitment in response to DNA damage

Bin Peng1, Jing Wang1, Yuan Hu1

  • 1Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing 100048, China.

Nucleic Acids Research
|May 23, 2015
PubMed

Insights

Proper DNA damage response relies on RNF168 and LSD1. CK2/WIP1-mediated LSD1 phosphorylation regulates RNF168-dependent 53BP1 recruitment, crucial for genome integrity and DNA repair.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Maintaining genome integrity through DNA damage response pathways is critical.
  • RNF168 is an E3 ligase essential for recruiting 53BP1 to DNA damage sites.
  • LSD1's role in DNA damage response involves H3K4me2 demethylation and H2A/H2AX ubiquitination.

Purpose of the Study:

  • To investigate the regulatory mechanism of LSD1 phosphorylation in DNA damage response.
  • To elucidate the interaction between LSD1, RNF168, and 53BP1.
  • To determine the functional significance of LSD1 phosphorylation in cellular sensitivity to DNA damaging agents.

Main Methods:

  • Investigated the interaction and phosphorylation of LSD1, RNF168, and 53BP1.
  • Utilized casein kinase 2 (CK2) and WIP1 in phosphorylation studies.
  • Employed phosphorylation-defective mutants to assess functional impact.

Main Results:

  • LSD1 phosphorylation at S131/S137 is regulated by CK2 and WIP1.
  • CK2-mediated LSD1 phosphorylation enhances interaction with RNF168, promoting 53BP1 ubiquitination and recruitment.
  • Phosphorylation-defective LSD1 mutants failed to rescue DNA damage sensitivity.

Conclusions:

  • LSD1 phosphorylation, modulated by CK2/WIP1, directly regulates RNF168-dependent 53BP1 recruitment.
  • This pathway is crucial for DNA damage response and cellular sensitivity to DNA damaging agents.
  • Findings provide insights into the molecular mechanisms governing genome stability.

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