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Nucleic Acids Research, 1994, Vol. 22, No. 22 4620-4624
© 1994

ENZYMOLOGY

Inhibition of gene-specific repair of alkylation damage in cells deplated of poly(ADP-ribose) polymerase

Tinna Stevnsner, Ruchuang Ding1, Mark Smulson1 and Vilhelm A. Bohr*

Laboratory of Molecular Genetics, National Institute of Aging, National Institutes of Health 4940 Eastern Avenue, Baltimore, MD 21224 1Department of Biochemistry and Molecular Biology, Georgetown University Medical School 3900 Reservoir Road NW, Washington, DC 20007, USA

*To whom correspondence should be addressed

Received August 4, 1994. Revised September 26, 1994. Accepted September 26, 1994.

The role of the enzyme poly(adenosine diphosphateribose) polymerase (PADPRP) in DNA repair at the level of the gene was investigated with human HeLa cells in which PADPRP antisense transcripts are inducible with dexamethasone. After such induction, the cellular content of PADPRP is reduced by 90%. DNA damage and its repair was studied in the essential dihydrofolate reductase (DHFR) gene after exposure of the cells to either ultraviolet (UV) irradiation or the alkylating agent nitrogen mustard. The expression of the antisense construct had no effect on gene-specific repair of UVinduced pyrimidine dimers. In contrast, induced antisense cells were deficient in the gene-specific repair of nitrogen mustard-induced leslons. Dexamethasone itself did not inhibit gene-specific repair in control cells. Thus, PADPRP appears to participate in the gene-specific repair of alkylation damage, but not in the repair of UV-induced pyrimidine dimers. Clonal survival assays revealed that cells depleted of PADPRP showed an increased susceptibility to nitrogen mustard, supporting the notion that repair of essential genes is critical for cellular survival.


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