Effects of Depletion of Dihydropyrimidine Dehydrogenase on Focus Formation and RPA Phosphorylation

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  • SOMEYA Masanori
    Department of Radiology, Sapporo Medical University, School of Medicine
  • SAKATA Koh-ichi
    Department of Radiology, Sapporo Medical University, School of Medicine
  • MATSUMOTO Yoshihisa
    Tokyo Institute of Technology, Research Laboratory for Nuclear Reactors
  • TAUCHI Hiroshi
    Department of Environmental Sciences, Faculty of Science, Ibaraki University
  • KAI Masahiro
    Department of Molecular Biology, Sapporo Medical University, School of Medicine
  • HAREYAMA Masato
    Department of Radiology, Sapporo Medical University, School of Medicine
  • FUKUSHIMA Masakazu
    Pharmacokinetics Research Laboratory, Taiho Pharmaceutical Co., Ltd.

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Gimeracil, an inhibitor of dihydropyrimidine dehydrogenase (DPYD), partially inhibits homologous recombination (HR) repair and has a radiosensitizing effect as well as enhanced sensitivity to Camptothecin (CPT). DPYD is the target protein for radiosensitization by Gimeracil. We investigated the mechanisms of sensitization of radiation and CPT by DPYD inhibition using DLD-1 cells treated with siRNA for DPYD. We investigated the focus formation of various kinds of proteins involved in HR and examined the phosphorylation of RPA by irradiation using Western blot analysis. DPYD depletion by siRNA significantly restrained the formation of radiation-induced foci of Rad51 and RPA, whereas it increased the number of foci of NBS1. The numbers of colocalization of NBS1 and RPA foci in DPYD-depleted cells after radiation were significantly smaller than in the control cells. These results suggest that DPYD depletion is attributable to decreased single-stranded DNA generated by the Mre11/Rad50/NBS1 complex-dependent resection of DNA double-strand break ends. The phosphorylation of RPA by irradiation was partially suppressed in DPYD-depleted cells, suggesting that DPYD depletion may partially inhibit DNA repair with HR by suppressing phosphorylation of RPA. DPYD depletion showed a radiosensitizing effect as well as enhanced sensitivity to CPT. The radiosensitizing effect of DPYD depletion plus CPT was the additive effect of DPYD depletion and CPT. DPYD depletion did not have a cell-killing effect, suggesting that DPYD depletion may not be so toxic. Considering these results, the combination of CPT and drugs that inhibit DPYD may prove useful for radiotherapy as a method of radiosensitization.

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