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RAD52 inactivation is synthetically lethal with deficiencies in BRCA1 and PALB2 in addition to BRCA2 through RAD51-mediated homologous recombination

Oncogene volume 32, pages 3552–3558 (2013)Cite this article

Abstract

Synthetic lethality is an approach to study selective cell killing based on genotype. Previous work in our laboratory has shown that loss of RAD52 is synthetically lethal with BRCA2 deficiency, while exhibiting no impact on cell growth and viability in BRCA2-proficient cells. We now show that this same synthetically lethal relationship is evident in cells with deficiencies in BRCA1 or PALB2, which implicates BRCA1, PALB2 and BRCA2 in an epistatic relationship with one another. When RAD52 was depleted in BRCA1- or PALB2-deficient cells, a severe reduction in plating efficiency was observed, with many abortive attempts at cell division apparent in the double-depleted background. In contrast, when RAD52 was depleted in a BRCA1- or PALB2-wildtype background, a negligible decrease in colony survival was observed. The frequency of ionizing radiation-induced RAD51 foci formation and double-strand break-induced homologous recombination (HR) was decreased by 3- and 10-fold, respectively, when RAD52 was knocked down in BRCA1- or PALB2-depleted cells, with minimal effect in BRCA1- or PALB2-proficient cells. RAD52 function was independent of BRCA1 status, as evidenced by the lack of any defect in RAD52 foci formation in BRCA1-depleted cells. Collectively, these findings suggest that RAD52 is an alternative repair pathway of RAD51-mediated HR, and a target for therapy in cells deficient in the BRCA1–PALB2–BRCA2 repair pathway.

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Acknowledgements

This work was supported in part by the Howard Hughes Medical Institute Medical Research Training Fellowship, the Radiological Society of North America Research Medical Student Grant (BHL) and by grants from the National Cancer Institute and the Susan G. Komen for the Cure (SNP).

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Authors and Affiliations

  1. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    B H Lok, A C Carley, B Tchang & S N Powell

  2. Department of Medicine and Department of Radiation Oncology, New York University School of Medicine, New York University Langone Medical Center, New York, NY, USA

    B H Lok

  3. Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA

    A C Carley

  4. College of Medicine, SUNY Downstate Medical Center, New York, NY, USA

    B Tchang

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  1. B H Lok
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Correspondence to S N Powell.

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Lok, B., Carley, A., Tchang, B. et al. RAD52 inactivation is synthetically lethal with deficiencies in BRCA1 and PALB2 in addition to BRCA2 through RAD51-mediated homologous recombination. Oncogene 32, 3552–3558 (2013). https://doi.org/10.1038/onc.2012.391

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