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DNA-PKcs suppresses illegitimate chromosome rearrangements

Jinglong Wang1, Cheyenne A Sadeghi1, Richard L Frock1

  • 1Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Nucleic Acids Research
|February 27, 2024
PubMed

Insights

DNA-PKcs inhibition in human cells increases translocations, revealing a bridge between human and mouse DNA repair mechanisms. This finding highlights DNA-PKcs

Area of Science:

  • Genetics
  • Molecular Biology
  • Cell Biology

Background:

  • Non-homologous end joining (NHEJ) and alternative end joining (A-EJ) are key DNA repair pathways involved in V(D)J recombination and chromosome translocations.
  • Previous research suggested distinct mechanisms for chromosome translocation repair in humans (NHEJ) and mice (A-EJ).
  • DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is crucial for NHEJ, synapsis formation, and downstream signaling.

Purpose of the Study:

  • To investigate the effect of DNA-PKcs inhibition on chromosome translocations in human cells.
  • To compare DNA repair mechanisms in human and mouse cells concerning DNA-PKcs activity.
  • To elucidate the role of DNA-PKcs in V(D)J recombination and illegitimate chromosome rearrangement.

Main Methods:

  • Partial and complete inhibition of DNA-PKcs in human cell lines.
  • Analysis of chromosome translocations and microhomology usage.
  • Genetic deletion of DNA-PKcs in mouse progenitor B cell lines.
  • Comparison of repair phenotypes with Ku70 and Lig4 deficiencies.

Main Results:

  • Partial DNA-PKcs inhibition in human cells increased translocations with residual NHEJ activity.
  • Complete DNA-PKcs inhibition promoted microhomology-mediated end joining (MMEJ), bridging human and mouse translocation mechanisms.
  • DNA-PKcs deletion in mouse cells impaired V(D)J recombination and increased translocations.
  • DNA-PKcs is essential for MMEJ in Lig4-deficient cells and suppresses illegitimate rearrangements.

Conclusions:

  • DNA-PKcs plays a conserved role in suppressing illegitimate chromosome rearrangements across species.
  • DNA-PKcs activity influences the choice between NHEJ and MMEJ in DNA repair.
  • The study reconciles distinct chromosome translocation mechanisms observed in human and mouse models.

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