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 β (polβ). Aberrant polβ expression is commonly found in human tumors and leads to inhibition of BER. Here, we show that truncated polβ variant (polβ-Δ)-expressing cells depend on homologous recombination (HR) for survival after IR, indicating that a considerable fraction of polβ-Δ-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 polβ-Δ-dependent radiosensitization. Consistent with the observed HR dependence and the known HR-modulating activity of ATM, polβ-Δ-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.
Highlights
One of the primary treatments for many types of cancer is ionizing radiation (IR), either as a single modality or in combination with other therapies
We have previously shown that expression of the dominantnegative polβ-Δ protein interferes with Base excision repair (BER) after IR and results in increased formation of residual double-strand breaks (DSB) as indicated by an increase in chromosome and chromatid aberrations [17]
Because we hypothesized that those lesions could have resulted from replication attempts at polβ-Δ–induced BER intermediates, we expected these lesions to arise after treatment with DNAdamaging agents creating damage similar to IR and requiring BER activity; one such agent is H2O2
Summary
One of the primary treatments for many types of cancer is ionizing radiation (IR), either as a single modality or in combination with other therapies. Local tumor control is strongly determined by intrinsic tumor radioresistance and normal tissue radiosensitivity, which can both limit success. Tumor-targeted strategies are needed that exploit tumor-specific characteristics and spare normal tissue. We present a novel tumordirected radiosensitization strategy, exploiting DNA repair deficiencies commonly found in tumors. Repair is initiated by DNA glycosylases that excise the damaged base, followed by AP-endonuclease (APE1) generating SSB intermediates [1, 2]. Direct radiation-induced SSBs require some end processing by enzymes such as PNK and Authors' Affiliation: Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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