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Efficient Repair of O⁶-Ethylguanine, but not O⁴-Ethylthymine or O²-Ethylthymine, Is Dependent upon O⁶-Alkylguanine-DNA Alkyltransferase and Nucleotide Excision Repair Activities in Human Cells

Department of Pathology, Duke University, Durham, North Carolina 27710 [S. M. B.], and Departments of Pathology and Environmental Sciences and Engineering, The University of North Carolina, Chapel Hill, North Carolina 27599 [T. R. S., J. A. S.]

The formation and persistence of O⁶-ethylguanine, O⁴-ethylthymine, and O²-ethylthymine were quantitated in the genomic DNA of human lymphoblasts exposed to 1.0 mM N-ethyl-N-nitrosourea using immunoslot-blot. The three cell lines used included one which lacks O⁶-alkylguanine-DNA alkyltransferase, one deficient in nucleotide excision repair, and a third which is competent in both of these repair pathways. The activity of O⁶-alkylguanine-DNA alkyltransferase was further modulated with O⁶-benzylguanine, a specific inhibitor of this protein. Repair of the O-ethylated thymines was slow and not related to either DNA repair phenotype. O⁶-Ethylguanine was repaired with a half-life of about 8 h in cells which expressed both O⁶-alkylguanine-DNA alkyltransferase and nucleotide excision repair functions. Cells expressing O⁶-alkylguanine-DNA alkyltransferase activity but lacking nucleotide excision repair showed only slow repair of O⁶-ethylguanine (half-life of O⁶-ethylguanine, 43 h), while cells lacking the alkyltransferase showed little or no repair of O⁶-ethylguanine regardless of nucleotide excision repair activity (half-lives of O⁶-ethylguanine, 53 to >100 h). We conclude that O⁶-alkylguanine-DNA alkyltransferase and nucleotide excision repair cooperate in the repair of O⁶-ethylguanine in human cells.

¹ To whom requests for reprints should be addressed, at Campus Box 7400, University of North Carolina, Chapel Hill, NC 27599.

Received 2/ 5/92. Accepted 2/27/92.

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