The Drosophila S3 multifunctional DNA repair/ribosomal protein protects Fanconi anemia cells against oxidative DNA damaging agents

Mark Kelley, R. Tritt, Y. Xu, S. New, B. Freie, D. Clapp, W. A. Deutsch

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 H2O2 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.

Original languageEnglish
Pages (from-to)107-119
Number of pages13
JournalMutation Research - DNA Repair
Volume485
Issue number2
DOIs
StatePublished - Mar 7 2001

Fingerprint

Fanconi Anemia
Ribosomal Proteins
DNA Repair
Drosophila
Repair
DNA
Mitomycin
Escherichia coli
DNA Damage
Complementary DNA
Endonucleases
Protective Agents
Lyases
Hydrogen Peroxide
Toxicity
Hypersensitivity
Proteins
Genes
Phenotype

Keywords

  • DNA repair
  • Fanconi anemia
  • Ribosomal
  • S3

ASJC Scopus subject areas

  • Toxicology
  • Genetics
  • Molecular Biology

Cite this

The Drosophila S3 multifunctional DNA repair/ribosomal protein protects Fanconi anemia cells against oxidative DNA damaging agents. / Kelley, Mark; Tritt, R.; Xu, Y.; New, S.; Freie, B.; Clapp, D.; Deutsch, W. A.

In: Mutation Research - DNA Repair, Vol. 485, No. 2, 07.03.2001, p. 107-119.

Research output: Contribution to journalArticle

@article{6fa4d99f87f5472eb9580dfd3af754f0,
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 H2O2 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.",
keywords = "DNA repair, Fanconi anemia, Ribosomal, S3",
author = "Mark Kelley and R. Tritt and Y. Xu and S. New and B. Freie and D. Clapp and Deutsch, {W. A.}",
year = "2001",
month = "3",
day = "7",
doi = "10.1016/S0921-8777(00)00067-7",
language = "English",
volume = "485",
pages = "107--119",
journal = "Mutation Research - DNA Repair",
issn = "0921-8777",
publisher = "Elsevier BV",
number = "2",

}

TY - JOUR

T1 - The Drosophila S3 multifunctional DNA repair/ribosomal protein protects Fanconi anemia cells against oxidative DNA damaging agents

AU - Kelley, Mark

AU - Tritt, R.

AU - Xu, Y.

AU - New, S.

AU - Freie, B.

AU - Clapp, D.

AU - Deutsch, W. A.

PY - 2001/3/7

Y1 - 2001/3/7

N2 - 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 H2O2 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.

AB - 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 H2O2 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.

KW - DNA repair

KW - Fanconi anemia

KW - Ribosomal

KW - S3

UR - http://www.scopus.com/inward/record.url?scp=0035820076&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035820076&partnerID=8YFLogxK

U2 - 10.1016/S0921-8777(00)00067-7

DO - 10.1016/S0921-8777(00)00067-7

M3 - Article

C2 - 11182542

AN - SCOPUS:0035820076

VL - 485

SP - 107

EP - 119

JO - Mutation Research - DNA Repair

JF - Mutation Research - DNA Repair

SN - 0921-8777

IS - 2

ER -