title: TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs.
abstract: Chain-terminating nucleoside analogs (CTNAs) 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 drugs. Here, we reveal the importance of tyrosyl-DNA phosphodiesterase 1 (TDP1) in the repair of nuclear and mitochondrial DNA damage induced by CTNAs. On investigating the effects of four CTNAs-acyclovir (ACV), cytarabine (Ara-C), zidovudine (AZT) and zalcitabine (ddC)-we show that TDP1 is capable of removing the covalently linked corresponding CTNAs 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 CTNA-induced DNA damage. As AZT and ddC are known to cause mitochondrial dysfunction, we examined whether TDP1 repairs the mitochondrial DNA damage they induced. We find that AZT and ddC treatment leads to greater depletion of mitochondrial DNA in Tdp1-/- cells. Thus, TDP1 seems to be critical for repairing nuclear and mitochondrial DNA damage caused by CTNAs.
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA, Department of Radiation Genetics, Kyoto University Graduate School of Medicine, Yoshida Konoe, Sakyo-ku, Kyoto 606-8501, Japan, NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA and Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Shar-yin N
authors.initials: SY
authors.lastname: Huang
authors.forename: Junko
authors.initials: J
authors.lastname: Murai
authors.forename: Ilaria
authors.initials: I
authors.lastname: Dalla Rosa
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Dexheimer
authors.forename: Alena
authors.initials: A
authors.lastname: Naumova
authors.forename: William H
authors.initials: WH
authors.lastname: Gmeiner
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D000212:Acyclovir / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism / Q000633:toxicity; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000633:toxicity*; D000998:Antiviral Agents / Q000378:metabolism / Q000633:toxicity*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects; D002478:Cells, Cultured; D002645:Chickens; D003561:Cytarabine / Q000378:metabolism / Q000633:toxicity; D004249:DNA Damage; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism; D017353:Gene Deletion; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D016047:Zalcitabine / Q000378:metabolism / Q000633:toxicity; D015215:Zidovudine / Q000378:metabolism / Q000633:toxicity
chemical_list: D019380:Anti-HIV Agents; D000964:Antimetabolites, Antineoplastic; D000998:Antiviral Agents; D004272:DNA, Mitochondrial; D003561:Cytarabine; D015215:Zidovudine; D016047:Zalcitabine; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human; D000212:Acyclovir