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TIE2-mediated tyrosine phosphorylation of H4 regulates DNA damage response by recruiting ABL1

Mohammad B Hossain1, Rehnuma Shifat1, David G Johnson2

  • 1Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Science Advances
|October 21, 2016
PubMed

Insights

Cancer cells use DNA repair to survive genotoxic therapies. The tyrosine kinase receptor TIE2 moves to the nucleus after radiation, enhancing DNA repair and promoting radioresistance by modifying histones.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cancer cells utilize DNA repair pathways to resist genotoxic therapies.
  • Tyrosine kinase receptors (TKRs) are known regulators of DNA repair mechanisms.
  • TIE2, a TKR, is overexpressed in human gliomas, correlating with malignancy.

Purpose of the Study:

  • To investigate the role of TIE2 in DNA repair and radioresistance in gliomas.
  • To elucidate the mechanism by which nuclear TIE2 influences DNA repair pathways.

Main Methods:

  • Analysis of TIE2 localization and function in glioma cells following ionizing radiation.
  • Biochemical assays to identify TIE2 interactions with DNA repair components.
  • Histone modification analysis, including phosphorylation studies.

Main Results:

  • Ionizing radiation induces nuclear translocation of TIE2 in glioma cells.
  • Nuclear TIE2 enhances the nonhomologous end-joining DNA repair pathway, leading to radioresistance.
  • Nuclear TIE2 phosphorylates histone H4 at tyrosine 51 (H4Y51), creating a binding site for ABL1.

Conclusions:

  • Nuclear TIE2 acts as a histone modifier and a sensor for genotoxic stress.
  • The H4Y51 phosphorylation is a novel signal linking genotoxic stress to DNA repair machinery via ABL1.
  • Targeting TIE2 may offer a strategy to overcome radioresistance in gliomas.
Keywords:
ABL1ANG1Cell biologyDNA repairNHEJTIE2oncogenes

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