title: Neuroprotection and repair of 3'-blocking DNA ends by glaikit (gkt) encoding Drosophila tyrosyl-DNA phosphodiesterase 1 (TDP1).
abstract: Tyrosyl-DNA phosphodiesterase (TDP1) is a phylogenetically conserved enzyme critical for the removal of blocking lesions at the 3' ends of DNA or RNA. This study analyzes the Drosophila TDP1 gene ortholog glaikit (gkt) and its possible role(s) in the repair of endogenous DNA lesions and neuroprotection. To do so, we studied a homozygous PiggyBac insertion (c03958) that disrupts the 5' UTR of gkt. Protein extracts of c03958 flies were defective in hydrolyzing 3'-DNA-tyrosyl residues, demonstrating that gkt is the Drosophila TDP1. Although the mutant is generally healthy and fertile, females exhibit reduced lifespan and diminished climbing ability. This phenotype was rescued by neuronal expression of TDP1. In addition, when c03958 larvae were exposed to bleomycin, an agent that produces oxidative DNA damage, or topoisomerase I-targeted drugs (camptothecin and a noncamptothecin indenoisoquinoline derivative, LMP-776), survivors displayed rough eye patches, which were rescued by neuronal expression of TDP1. Our study establishes that gkt is the Drosophila TDP1 gene, and that it is critical for neuroprotection, normal longevity, and repair of damaged DNA.
authors.affiliation: Section on Molecular Genetics, Laboratory of Molecular Biology, National Institute of Mental Health and dongyu.guo@fda.hhs.gov pommier@nih.gov.
authors.forename: DongYu
authors.initials: D
authors.lastname: Guo
authors.affiliation: Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Dexheimer
authors.affiliation: Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 dongyu.guo@fda.hhs.gov pommier@nih.gov.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.affiliation: Section on Molecular Genetics, Laboratory of Molecular Biology, National Institute of Mental Health and.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Nash
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology; D052117:Benzodioxoles / Q000009:adverse effects; D001761:Bleomycin / Q000009:adverse effects / Q000494:pharmacology; D002166:Camptothecin / Q000009:adverse effects / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D005260:Female; D006868:Hydrolysis / Q000187:drug effects; D007546:Isoquinolines / Q000009:adverse effects; D008136:Longevity; D008297:Male; D016254:Mutagenesis, Insertional; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D059004:Topoisomerase I Inhibitors / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D000903:Antibiotics, Antineoplastic; D052117:Benzodioxoles; D029721:Drosophila Proteins; D007546:Isoquinolines; D009419:Nerve Tissue Proteins; D059004:Topoisomerase I Inhibitors; C416215:gkt protein, Drosophila; D001761:Bleomycin; D010727:Phosphoric Diester Hydrolases; C578795:indimitecan; D002166:Camptothecin
keywords: DNA repair; aging; fly; neuroscience; topoisomerase