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53BP1-RIF1 and DNA-PKcs show distinct genetic interactions with diverse chromosomal break repair outcomes

Author

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  • Kaela Makins

    (Beckman Research Institute of City of Hope, Department of Cancer Genetics and Epigenetics
    Beckman Research Institute of the City of Hope, Irell and Manella Graduate School of Biological Sciences)

  • Metztli Cisneros-Aguirre

    (Beckman Research Institute of City of Hope, Department of Cancer Genetics and Epigenetics
    Beckman Research Institute of the City of Hope, Irell and Manella Graduate School of Biological Sciences
    Salk Institute for Biological Sciences)

  • Felicia Wednesday Lopezcolorado

    (Beckman Research Institute of City of Hope, Department of Cancer Genetics and Epigenetics)

  • Jeremy M. Stark

    (Beckman Research Institute of City of Hope, Department of Cancer Genetics and Epigenetics
    Beckman Research Institute of the City of Hope, Irell and Manella Graduate School of Biological Sciences)

Abstract

53BP1 accumulates at DNA double strand breaks (DSBs) and is implicated in non-homologous end joining (NHEJ), but the genetic interplay of 53BP1 with the NHEJ pathway (e.g., DNA-PKcs) is poorly understood. We examine blunt DSB NHEJ of Cas9 DSBs, which is dependent on core NHEJ factors, and find that loss of 53BP1 does not affect such repair but causes a reduction when combined with DNA-PKcs disruption. In contrast, disrupting 53BP1 and DNA-PKcs, alone and together, has similar effects on the type of deletion mutation (increase in microhomology deletions). We find similar effects with RIF1, such that 53BP1-RIF1 appear to play a backup role for DNA-PKcs during blunt DSB NHEJ, but function in the same pathway to suppress microhomology deletions. Finally, DNA-PKcs kinase inhibition causes increased radiosensitivity and homology-directed repair that is not additive with loss of 53BP1. Altogether, 53BP1-RIF1 and DNA-PKcs show distinct genetic interactions with diverse DSB repair outcomes.

Suggested Citation

  • Kaela Makins & Metztli Cisneros-Aguirre & Felicia Wednesday Lopezcolorado & Jeremy M. Stark, 2025. "53BP1-RIF1 and DNA-PKcs show distinct genetic interactions with diverse chromosomal break repair outcomes," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65329-3
    DOI: 10.1038/s41467-025-65329-3
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