title: The Drosophila S3 multifunctional DNA repair/ribosomal protein protects Fanconi anemia cells against oxidative DNA damaging agents.
abstract: Cells harvested from Fanconi anemia (FA) patients show an increased hypersensitivity to the multifunctional DNA damaging agent mitomycin C (MMC), which causes cross-links in DNA as well as 7,8-dihydro-8-oxoguanine (8-oxoG) adducts indicative of escalated oxidative DNA damage. We show here that the Drosophila multifunctional S3 cDNA, which encodes an N-glycosylase/apurinic/apyrimidinic (AP) lyase activity was found to correct the FA Group A (FA(A)) and FA Group C (FA(C)) sensitivity to MMC and hydrogen peroxide (H2O2). Furthermore, the Drosophila S3 cDNA was shown to protect AP endonuclease deficient E. coli cells against H(2)O(2) and MMC, and also protect 8-oxoG repair deficient mutM E. coli strains against MMC and H2O2 cell toxicity. Conversely, the human S3 protein failed to complement the AP endonuclease deficient E. coli strain, most likely because it lacks N-glycosylase activity for the repair of oxidatively-damaged DNA bases. Although the human S3 gene is clearly not the genetic alteration in FA cells, our results suggest that oxidative DNA damage is intimately involved in the overall FA phenotype, and the cytotoxic effect of selective DNA damaging agents in FA cells can be overcome by trans-complementation with specific DNA repair cDNAs. Based on these findings, we would predict other oxidative repair proteins, or oxidative scavengers, could serve as protective agents against the oxidative DNA damage that occurs in FA.
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, 702 Barnhill Dr., Room 2600, Indianapolis, IN 46202, USA. mkelley@iupui.edu
authors.forename: M R
authors.initials: MR
authors.lastname: Kelley
authors.forename: R
authors.initials: R
authors.lastname: Tritt
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: S
authors.initials: S
authors.lastname: New
authors.forename: B
authors.initials: B
authors.lastname: Freie
authors.forename: D W
authors.initials: DW
authors.lastname: Clapp
authors.forename: W A
authors.initials: WA
authors.lastname: Deutsch
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D019757:Carbon-Oxygen Lyases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D043382:DNA-Formamidopyrimidine Glycosylase; D043223:Deoxyribonuclease IV (Phage T4-Induced); D004330:Drosophila; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005816:Genetic Complementation Test; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D016685:Mitomycin / Q000494:pharmacology; D009699:N-Glycosyl Hydrolases / Q000172:deficiency / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D012190:Retroviridae / Q000235:genetics; D012269:Ribosomal Proteins / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D018952:Antigens, CD34; D003432:Cross-Linking Reagents; D018076:DNA, Complementary; D029968:Escherichia coli Proteins; D012269:Ribosomal Proteins; C044152:ribosomal protein S3; D016685:Mitomycin; C024829:8-hydroxyguanine; D006147:Guanine; D006861:Hydrogen Peroxide; D043223:Deoxyribonuclease IV (Phage T4-Induced); C468972:endonuclease IV, E coli; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; C468610:DNA-formamidopyrimidine glycosylase, E coli; D019757:Carbon-Oxygen Lyases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase