Nucleic Acids Research, Vol 26, Issue 11 2644-2649, Copyright © 1998 by Oxford University Press
C Trucco, FJ Oliver, G de Murcia and J Menissier-de Murcia
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
gamma-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.
ARTICLES
DNA repair defect in poly(ADP-ribose) polymerase-deficient cell lines
UPR 9003 du Centre National de la Recherche Scientifique, Laboratoire Conventionne avec le Commissariat a l'Energie Atomique, Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sebastien Brant, F-67400 Illkirch-Graffenstad, France.
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O. I. Lavrik, R. Prasad, R. W. Sobol, J. K. Horton, E. J. Ackerman, and S. H. Wilson Photoaffinity Labeling of Mouse Fibroblast Enzymes by a Base Excision Repair Intermediate. EVIDENCE FOR THE ROLE OF POLY(ADP-RIBOSE) POLYMERASE-1 IN DNA REPAIR J. Biol. Chem., June 29, 2001; 276(27): 25541 - 25548. [Abstract] [Full Text] [PDF]
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C. M. Simbulan-Rosenthal, D. H. Ly, D. S. Rosenthal, G. Konopka, R. Luo, Z.-Q. Wang, P. G. Schultz, and M. E. Smulson Misregulation of gene expression in primary fibroblasts lacking poly(ADP-ribose) polymerase PNAS, October 10, 2000; 97(21): 11274 - 11279. [Abstract] [Full Text] [PDF]
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