️ Episode 216: 53BP1-RIF1 and DNA-PKcs: distinct interactions in chromosomal break repair

In this episode of PaperCast Base by Base, we explore This episode reviews a study showing that 53BP1-RIF1 and DNA-PKcs have different genetic relationships across blunt end joining, deletion patterns, HDR, and radiosensitivity

Study Highlights:
Using EJ7-GFP and MA-del reporters in HEK293 cells, loss of 53BP1 alone did not reduce blunt No Indel EJ but amplified the decrease caused by DNA-PKcs kinase inhibition (M3814) or PRKDC knockout. Disruption of 53BP1 or RIF1, and DNA-PKcs inhibition or loss, each caused a similar shift toward deletions with increased microhomology and reduced non-microhomology deletions, with combined disruption not additive. 53BP1 loss reduced blunt EJ efficiency in XLF-deficient cells and the deletion pattern of the 53BP1/XLF double mutant resembled that of 53BP1 loss alone. DNA-PKcs kinase inhibition produced marked increases in HDR and radiosensitivity that differed from genetic DNA-PKcs loss and were not fully additive with 53BP1 or RIF1 loss.

Conclusion:
53BP1-RIF1 act as a backup to DNA-PKcs for blunt DSB end joining but function in the same pathway as DNA-PKcs to limit microhomology-mediated deletions, while DNA-PKcs kinase inhibition broadly perturbs repair outcomes and increases radiosensitivity

Music:
Enjoy the music based on this article at the end of the episode.

Reference:
Makins K, Cisneros-Aguirre M, Lopezcolorado FW & Stark JM. 53BP1-RIF1 and DNA-PKcs show distinct genetic interactions with diverse chromosomal break repair outcomes. Nature Communications. 2025;16:10 361. https://doi.org/10.1038/s41467-025-65329-3

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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