Radiosensitization by a dominant negative to DNA polymerase beta is DNA polymerase beta-independent and XRCC1-dependent.
until further notice
SourceRadiotherapy and Oncology, 76, 2, (2005), pp. 123-128
Article / Letter to editor
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Radiotherapy and Oncology
SubjectUMCN 1.3: Tumor microenvironment
BACKGROUND AND PURPOSE: DNA base damages and single strand breaks after ionizing radiation are repaired by base excision repair (BER) and single strand break repair (SSBR), with both DNA polymerase beta (polbeta) and XRCC1 playing key roles. We previously showed that a dominant negative to polbeta (polbetaDN) sensitized human tumor cells to ionizing radiation. However, polbeta-deficient cells, in contrast to XRCC1-deficient cells, are not more radiosensitive. The purpose of the present study was to further elucidate the mechanism of action of the polbetaDN to better understand the roles of BER and SSBR in determining radiosensitivity. MATERIALS AND METHODS: Mouse embryonic fibroblasts, both polbeta wildtype and knockout, and hamster XRCC1-deficient EM9 cells together with its parental line, were transfected with the polbetaDN. Clones with equal polbetaDN expression levels were selected and used in clonogenic assays to determine radiosensitivity. RESULTS: Radiosensitization of polbeta deficient cells by the polbetaDN is shown here, demonstrating inhibition of a polbeta-independent pathway. In addition, we observed radiosensitization of wildtype hamster cells but no radiosensitization of the XRCC1-deficient EM9 cells. CONCLUSIONS: The polbetaDN acts independently of polbeta status and inhibits a pathway, which is dependent on XRCC1, consistent with inhibition of BER and/or SSBR. The data further indicate involvement of other polymerases, which are inhibited by polbetaDN. Finally, they demonstrate that inhibition of BER and SSBR can increase radiosensitivity, with potential clinical relevance.
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