DNA Repair Defect in Poly(ADP-ribose) Polymerase-deficient Cell Lines

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 1998 May 21

PMID 9592149

Citations 125

Authors

C Trucco

F J Oliver

G de Murcia

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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