Abstract C79: TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs.

Abstract

Abstract Nucleoside analogs (NAs) that cause stalling or premature termination of DNA replication forks are widely used as anticancer and antiviral drugs. However, it is not well understood how cells repair the DNA damage induced by these chain-terminating NAs. Here we reveal the importance of tyrosyl-DNA phosphodiesterase 1 (TDP1) in the repair of nuclear and mitochondrial DNA damage induced by chain-terminating NAs. Upon investigating the effects of four NAs: acyclovir (ACV), cytarabine (Ara-C), zidovudine (AZT) and zalcitabine (ddC), we show that TDP1 is capable of removing the covalently-linked corresponding NAs from DNA 3’-ends. We also show that Tdp1–/– cells are hypersensitive and accumulate more DNA damage when treated with ACV and Ara-C, implicating TDP1 in repairing NA-induced DNA damage. Since AZT and ddC are known to cause mitochondrial dysfunction, we examined whether TDP1 repairs the mitochondrial DNA damage they induced. We found that AZT and ddC treatment leads to greater depletion of mitochondrial DNA in Tdp1–/– cells. Thus, TDP1 appears critical for repairing nuclear and mitochondrial DNA damage caused by chain-terminating NAs. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C79. Citation Format: Shar-Yin N. Huang, Junko Murai, Ilaria Dalla Rosa, Thomas S. Dexheimer, William H. Gmeiner, Yves Pommier. TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C79.