Pharmacological boost of DNA damage response and repair by enhanced biogenesis of DNA damage response RNAs.

Ubaldo Gioia, Sofia Francia, Matteo Cabrini, Silvia Brambillasca, Flavia Michelini, Corey W Jones-Weinert, Fabrizio d'Adda di Fagagna

Scientific reports 2019 Apr 23

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A novel class of small non-coding RNAs called DNA damage response RNAs (DDRNAs) generated at DNA double-strand breaks (DSBs) in a DROSHA- and DICER-dependent manner has been shown to regulate the DNA damage response (DDR). Similar molecules were also reported to guide DNA repair. Here, we show that DDR activation and DNA repair can be pharmacologically boosted by acting on such non-coding RNAs. Cells treated with enoxacin, a compound previously demonstrated to augment DICER activity, show stronger DDR signalling and faster DNA repair upon exposure to ionizing radiations compared to vehicle-only treated cells. Enoxacin stimulates DDRNA production at chromosomal DSBs and at dysfunctional telomeres, which in turn promotes 53BP1 accumulation at damaged sites, therefore in a miRNA-independent manner. Increased 53BP1 occupancy at DNA lesions induced by enoxacin ultimately suppresses homologous recombination, channelling DNA repair towards faster and more accurate non-homologous end-joining, including in post-mitotic primary neurons. Notably, augmented DNA repair stimulated by enoxacin increases the survival also of cancer cells treated with chemotherapeutic agents.

Citation

Ubaldo Gioia, Sofia Francia, Matteo Cabrini, Silvia Brambillasca, Flavia Michelini, Corey W Jones-Weinert, Fabrizio d'Adda di Fagagna. Pharmacological boost of DNA damage response and repair by enhanced biogenesis of DNA damage response RNAs. Scientific reports. 2019 Apr 23;9(1):6460