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

Kaela Makins, Metztli Cisneros-Aguirre, Felicia Wednesday Lopezcolorado and Jeremy M. Stark ()
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Kaela Makins: Beckman Research Institute of City of Hope, Department of Cancer Genetics and Epigenetics
Metztli Cisneros-Aguirre: Beckman Research Institute of City of Hope, Department of Cancer Genetics and Epigenetics
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

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65329-3

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