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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
Summary
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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