Abstract
Effective DNA repair enables cancer cells to survive DNA damage induced by chemotherapeutic or radiotherapeutic treatments. Therefore, inhibiting DNA repair pathways is a promising therapeutic strategy for increasing the efficacy of such treatments. In this study, we found that dihydrocoumarin (DHC), a flavoring agent, causes deficiencies in double-stand break (DSB) repair and prolonged DNA damage checkpoint recovery in yeast. Following DNA damage, Rad52 recombinase was revealed to be inhibited by DHC, which results in deficiencies in DSB repair and prolonged DNA damage checkpoint recovery. The deletion of RPD3, a class I histone deacetylase (HDAC), was found to mimic DHC-induced suppression of Rad52 expression, suggesting that the HDAC inhibitor activity of DHC is critical to DSB repair and DNA damage sensitivity. Overall, our findings delineate the regulatory mechanisms of DHC in DSB repair and suggest that it might potentially be used as an inhibitor of the DNA repair pathway in human cells.
Highlights
Chemotherapy and radiotherapy are major cancer treatments that generate DNA damage in cancer cells [1,2,3]
Using the single-strand annealing (SSA) system, the results revealed that DHC sensitizes yeast cells to DNA damage by regulating Rad52 and influences damage-induced apoptosis and autophagy
Because DNA double-stand break (DSB) are generated at unpredictable locations after DNA damage agent treatment, it is hard to address DNA repair in these sites following such treatments
Summary
Chemotherapy and radiotherapy are major cancer treatments that generate DNA damage in cancer cells [1,2,3]. Tel and Mec (ATM and ATR in human, respectively) initiate the DNA damage checkpoint [16,17] Upon their recruitment to DNA, Mec and its binding partner Ddc (ATRIP in human) phosphorylate a group of targets, including histone H2A. HR is an accurate repair pathway, whereas the NHEJ pathways are less accurate and potentially cause DNA rearrangements [20,21] In both cancer and budding yeast, HR is the major repair pathway for overcoming DSB lesions [22,23]. Because HDAC inhibitors inhibit the DNA damage response (DDR) [29,30], DHC might suppress the DNA repair machinery by inhibiting HDAC activity These activities have not been identified due to the sequence-independent nature of radiation or chemotherapy drug-induced damage. Our results support the notion of targeting DNA repair with DHC, which could provide a valuable model for identifying the effects of the combined use of DHC and radio- or chemotherapy
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