The Drosophila melanogaster DNA Ligase IV Gene Plays a Crucial Role in the Repair of Radiation-Induced DNA Double-Strand Breaks and Acts Synergistically with Rad54

Marcin M. Gorski, J. C J Eeken, A. W M De Jong, Ilse Klink, Marjan Loos, Ron J. Romeijn, Bert L. Van Veen, Leon H. Mullenders, Wouter Ferro, Albert Pastink

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

DNA Ligase IV has a crucial role in double-strand break (DSB) repair through nonhomologous end joining (NHEJ). Most notably, its inactivation leads to embryonic lethality in mammals. To elucidate the role of DNA Ligase IV (Lig4) in DSB repair in a multicellular lower eukaryote, we generated viable Lig4-deficient Drosophila strains by P-element-mediated mutagenesis. Embryos and larvae of mutant lines are hypersensitive to ionizing radiation but hardly so to methyl methanesulfonate (MMS) or the crosslinking agent cis-diamminedichloroplatinum (cisDDP). To determine the relative contribution of NHEJ and homologous recombination (HR) in Drosophila, Lig4; Rad54 double-mutant flies were generated. Survival studies demonstrated that both HR and NHEJ have a major role in DSB repair. The synergistic increase in sensitivity seen in the double mutant, in comparison with both single mutants, indicates that both pathways partially overlap. However, during the very first hours after fertilization NHEJ has a minor role in DSB repair after exposure to ionizing radiation. Throughout the first stages of embryogenesis of the fly, HR is the predominant pathway in DSB repair. At late stages of development NHEJ also becomes less important. The residual survival of double mutants after irradiation strongly suggests the existence of a third pathway for the repair of DSBs in Drosophila.

Original languageEnglish
Pages (from-to)1929-1941
Number of pages13
JournalGenetics
Volume165
Issue number4
Publication statusPublished - Dec 2003

Fingerprint

Double-Stranded DNA Breaks
Homologous Recombination
Drosophila melanogaster
Drosophila
Radiation
Ionizing Radiation
Diptera
Genes
Methyl Methanesulfonate
Eukaryota
Fertilization
Mutagenesis
Cisplatin
Embryonic Development
Larva
Mammals
Embryonic Structures
DNA Ligase ATP

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Gorski, M. M., Eeken, J. C. J., De Jong, A. W. M., Klink, I., Loos, M., Romeijn, R. J., ... Pastink, A. (2003). The Drosophila melanogaster DNA Ligase IV Gene Plays a Crucial Role in the Repair of Radiation-Induced DNA Double-Strand Breaks and Acts Synergistically with Rad54. Genetics, 165(4), 1929-1941.

The Drosophila melanogaster DNA Ligase IV Gene Plays a Crucial Role in the Repair of Radiation-Induced DNA Double-Strand Breaks and Acts Synergistically with Rad54. / Gorski, Marcin M.; Eeken, J. C J; De Jong, A. W M; Klink, Ilse; Loos, Marjan; Romeijn, Ron J.; Van Veen, Bert L.; Mullenders, Leon H.; Ferro, Wouter; Pastink, Albert.

In: Genetics, Vol. 165, No. 4, 12.2003, p. 1929-1941.

Research output: Contribution to journalArticle

Gorski, MM, Eeken, JCJ, De Jong, AWM, Klink, I, Loos, M, Romeijn, RJ, Van Veen, BL, Mullenders, LH, Ferro, W & Pastink, A 2003, 'The Drosophila melanogaster DNA Ligase IV Gene Plays a Crucial Role in the Repair of Radiation-Induced DNA Double-Strand Breaks and Acts Synergistically with Rad54', Genetics, vol. 165, no. 4, pp. 1929-1941.
Gorski, Marcin M. ; Eeken, J. C J ; De Jong, A. W M ; Klink, Ilse ; Loos, Marjan ; Romeijn, Ron J. ; Van Veen, Bert L. ; Mullenders, Leon H. ; Ferro, Wouter ; Pastink, Albert. / The Drosophila melanogaster DNA Ligase IV Gene Plays a Crucial Role in the Repair of Radiation-Induced DNA Double-Strand Breaks and Acts Synergistically with Rad54. In: Genetics. 2003 ; Vol. 165, No. 4. pp. 1929-1941.
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abstract = "DNA Ligase IV has a crucial role in double-strand break (DSB) repair through nonhomologous end joining (NHEJ). Most notably, its inactivation leads to embryonic lethality in mammals. To elucidate the role of DNA Ligase IV (Lig4) in DSB repair in a multicellular lower eukaryote, we generated viable Lig4-deficient Drosophila strains by P-element-mediated mutagenesis. Embryos and larvae of mutant lines are hypersensitive to ionizing radiation but hardly so to methyl methanesulfonate (MMS) or the crosslinking agent cis-diamminedichloroplatinum (cisDDP). To determine the relative contribution of NHEJ and homologous recombination (HR) in Drosophila, Lig4; Rad54 double-mutant flies were generated. Survival studies demonstrated that both HR and NHEJ have a major role in DSB repair. The synergistic increase in sensitivity seen in the double mutant, in comparison with both single mutants, indicates that both pathways partially overlap. However, during the very first hours after fertilization NHEJ has a minor role in DSB repair after exposure to ionizing radiation. Throughout the first stages of embryogenesis of the fly, HR is the predominant pathway in DSB repair. At late stages of development NHEJ also becomes less important. The residual survival of double mutants after irradiation strongly suggests the existence of a third pathway for the repair of DSBs in Drosophila.",
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