Specific killing of BRCA1-deficient cancer cells by depletion of EXO1

How to Cite

van de Kooij, B., Schreuder, A., Pavani, R. S., Garzero, V., van Hoeck, A., San Martin Alonso, M., Koerse, D., Boom, J., Mei, H., Cuppen, E. P. J. G., Nussenzweig, A., van Attikum, H., & Noordermeer, S. M. (2023). Specific killing of BRCA1-deficient cancer cells by depletion of EXO1. Spanish Journal of Environmental Mutagenesis and Genomics, 27(1), 60. Retrieved from https://www.ojs.diffundit.com/index.php/sema/article/view/1384


BRCA1 and BRCA2 are essential genome maintenance factors that function in the repair of DNA Double-Strand Breaks (DSBs) by homologous recombination (HR). Cancer patients that carry tumors with loss-of-function mutations in BRCA1 or BRCA2 often benefit from treatment with PARP inhibitor therapy, which specifically kills HR-deficient tumor cells. However, clinical responses are rarely long-lasting due to resistance to PARP inhibitor treatment. We therefore sought to identify novel therapeutic opportunities to treat HR-deficient tumors. Our studies revealed that genetic inactivation of the exonuclease EXO1 is severely toxic to BRCA1-deficient cells, but not to BRCA1-proficient cells. Mechanistically, our data suggest show that loss of EXO1 results in DSB formation, potentially due to a defect in the maturation of Okazaki fragments. BRCA1/EXO1 double-deficient cells are severely compromised in their capacity to repair these DSBs, resulting in genomic instability and cell death. Taken together, we have uncovered EXO1 as a novel synthetic lethal target with therapeutic potential to treat patients carrying BRCA1-deficient tumors.

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Copyright (c) 2023 Spanish Journal of Environmental Mutagenesis and Genomics


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