Targeted radiosensitization of cells expressing truncated DNA polymerase {beta}.

Abstract:

Ionizing radiation (IR) is an effective anticancer treatment, although failures still occur. To improve radiotherapy, tumor-targeted strategies are needed to increase radiosensitivity of tumor cells, without influencing normal tissue radiosensitivity. Base excision repair (BER) and single-strand break repair (SSBR) contribute to the determination of sensitivity to IR. A crucial protein in BER/SSBR is DNA polymerase beta (polbeta). Aberrant polbeta expression is commonly found in human tumors and leads to inhibition of BER. Here, we show that truncated polbeta variant (polbeta-Delta)-expressing cells depend on homologous recombination (HR) for survival after IR, indicating that a considerable fraction of polbeta-Delta-induced lesions are subject to repair by HR. Increased sensitization was found not to result from involvement in DNA-dependent protein kinase-dependent nonhomologous end joining, the other major double-strand break repair pathway. Caffeine and the ATM inhibitor Ku55933 cause polbeta-Delta-dependent radiosensitization. Consistent with the observed HR dependence and the known HR-modulating activity of ATM, polbeta-Delta-expressing cells showed increased radiosensitization after BRCA2 knockdown that is absent under ATM-inhibited conditions. Our data suggest that treatment with HR modulators is a promising therapeutic strategy for exploiting defects in the BER/SSBR pathway in human tumors.

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