DNA repair defect in poly(ADP-ribose) polymerase-deficient cell lines

To investigate the physiological function of poly(ADP-ribose) polymerase (PARP), we used a gene targeting strategy to generate mice lacking a functional PARP gene. These PARP−/− mice were exquisitely sensitive to the monofunctional-alkylating agent N-methyl-N-nitrosourea (MNU) and γ-irradiation. In...

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Bibliographic Details
Published in:Nucleic acids research 1998-06, Vol.26 (11), p.2644-2649
Main Authors: Trucco, Carlotta, Javier Oliver, F., de Murcia, Gilbert, Ménissier-de Murcia, Josiane
Format: Article
Language:English
Subjects:
Animals
Biochemistry, Molecular Biology
Cell Division
Cell Survival
Cells, Cultured
Chromosome Aberrations
DNA Repair
Fibroblasts
Fibroblasts - enzymology
G2 Phase
Life Sciences
Mice
Mice, Knockout
Mitosis
Poly(ADP-ribose) Polymerases
Poly(ADP-ribose) Polymerases - genetics
Poly(ADP-ribose) Polymerases - physiology
Structural Biology
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Summary:To investigate the physiological function of poly(ADP-ribose) polymerase (PARP), we used a gene targeting strategy to generate mice lacking a functional PARP gene. These PARP−/− mice were exquisitely sensitive to the monofunctional-alkylating agent N-methyl-N-nitrosourea (MNU) and γ-irradiation. In this report, we have analysed the cause of this increased lethality using primary and/or spontaneously immortalized mouse embryonic fibroblasts (MEFs) derived from PARP−/− mice. We found that the lack of PARP renders cells significantly more sensitive to methylmethanesulfonate (MMS), causing cell growth retardation, G2/M accumulation and chromosome instability. An important delay in DNA strand-break resealing was observed following treatment with MMS. This severe DNA repair defect appears to be the primary cause for the observed cytoxicity of monofunctional-alkylating agents, leading to cell death occurring after G2/M arrest. Cell viability following MMS treatment could be fully restored after transient expression of the PARP gene. Altogether, these results unequivocally demonstrate that PARP is required for efficient base excision repair in vivo and strengthens the role of PARP as a survival factor following genotoxic stress.
ISSN:0305-1048
1362-4962
1362-4962
DOI:10.1093/nar/26.11.2644