Cells deficient in DNA polymerase β are hypersensitive to alkylating agent-induced apoptosis and chromosomal breakage

DNA polymerase beta (beta-pol), which is involved in base excision repair, was investigated for its role in protection of cells against various genotoxic agents and cytostatic drugs using beta-pol knockout mouse fibroblasts. We show that cells lacking beta-pol are highly sensitive to induction of ap...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1999-04, Vol.59 (7), p.1544-1551
Main Authors: OCHS, K, SOBOL, R. W, WILSON, S. H, KAINA, B
Format: Article
Language:English
Subjects:
Alkylating Agents - toxicity
Animals
Antineoplastic agents
Apoptosis - drug effects
Biological and medical sciences
Chemotherapy
Chromosome Aberrations
DNA Damage
DNA Polymerase beta - physiology
DNA Repair
Medical sciences
Methyl Methanesulfonate - toxicity
Methylnitronitrosoguanidine - toxicity
Mice
Mice, Knockout
Necrosis
Pharmacology. Drug treatments
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Summary:DNA polymerase beta (beta-pol), which is involved in base excision repair, was investigated for its role in protection of cells against various genotoxic agents and cytostatic drugs using beta-pol knockout mouse fibroblasts. We show that cells lacking beta-pol are highly sensitive to induction of apoptosis and chromosomal breakage by methylating agents, such as N-methyl-N'-nitro-N-nitrosoguanidine and methyl methanesulfonate and the cross-linking antineoplastic drugs mitomycin C and mafosfamide. The cross-sensitivity between the agents observed suggests that beta-pol is involved in repair not only of DNA methylation lesions but also of other kinds of DNA damage induced by various cytostatic drugs. Cells deficient in beta-pol were not hypersensitive to cisplatin, melphalan, benzo(a)pyrene diol epoxide, chloroethylnitrosourea, or UV light. Because both established and primary beta-pol knockout fibroblasts displayed the hypersensitive phenotype, which, moreover, was complemented by transfection with a beta-pol expression vector, the alkylating agent hypersensitivity can clearly be attributed to the beta-pol deficiency. The results demonstrate that beta-pol-driven base excision repair is highly important for protection of cells against cell killing due to apoptosis and induced chromosomal breakage and suggest that incompletely repaired DNA damage causes chromosomal changes and may act as a trigger of DNA damage-induced apoptosis.
ISSN:0008-5472
1538-7445