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Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants

Oncogene volume 19, pages 5788–5800 (2000)Cite this article

Abstract

The radiosensitizing effect of caffeine has been associated with the disruption of multiple DNA damage-responsive cell cycle checkpoints, but several lines of evidence also implicate inhibition of DNA repair. The role of DNA repair inhibition in caffeine radiosensitization remains uncharacterized, and it is unknown which repair process, or lesion, is affected. We show that a radiosensitive cell line, mutant for the RAD51 homolog XRCC2 and defective in homologous recombination repair (HRR), displays significantly diminished caffeine radiosensitization that can be restored by expression of XRCC2. Despite the reduced radiosensitization, caffeine effectively abrogates checkpoints in S and G2 phases in XRCC2 mutant cells indicating that checkpoint abrogation is not sufficient for radiosensitization. Another radiosensitive line, mutant for XRCC3 and defective in HRR, similarly shows reduced caffeine radiosensitization. On the other hand, a radiosensitive mutant (irs-20) of DNA-PKcs with a defect in non-homologous endjoining (NHEJ) is radiosensitized by caffeine to an extent comparable to wild-type cells. In addition, rejoining of radiation-induced DNA DSBs, that mainly reflects NHEJ, remains unaffected by caffeine in XRCC2 and XRCC3 mutants, or their wild-type counterparts. These observations suggest that caffeine targets steps in HRR but not in NHEJ and that abrogation of checkpoint response is not sufficient to explain radiosensitization. Indeed, immortalized fibroblasts from AT patients show caffeine radiosensitization despite the checkpoint defects associated with ATM mutation. We propose that caffeine radiosensitization is mediated by inhibition of stages in DNA DSB repair requiring HRR and that checkpoint disruption contributes by allowing these DSBs to transit into irreparable states. Thus, checkpoints may contribute to genomic stability by promoting error-free HRR.

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Acknowledgements

Supported by NCI Grant 2RO1 CA42026, 56706 and P30-CA56036 awarded from NIH, DHHS and by NASA's Biomedical Research and Countermeasures Program and the Advanced Human Support Technology Program under NRA's 96-HEDS-04 and 96-HEDS-05. The authors are indebted to Drs Colin Arlett, Joel Bedford and Larry Thompson for cells. Special thanks go to Ms Nancy Mott for help in the preparation of the manuscript.

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  1. Department of Radiation Oncology of Kimmel Cancer Center, Jefferson Medical College, Philadelphia, PA 19107, Pennsylvania, USA

    Nesrin A Asaad, Zhao-Chong Zeng, Jun Guan & George Iliakis

  2. Medical Research Council, Radiation and Genome Stability Unit, Harwell, OX11 ORD, Oxfordshire, UK

    John Thacker

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Asaad, N., Zeng, ZC., Guan, J. et al. Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants. Oncogene 19, 5788–5800 (2000). https://doi.org/10.1038/sj.onc.1203953

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