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A Mutator Phenotype Characterizes One of Two Complementation Groups in Human Cells Tolerant to Methylation Damage¹

Istituto Superiore di Sanita', Laboratory of Comparative Toxicology and Ecotoxicology, Viale Regina Elena 299, 00161 Rome, Italy

Sixty % of clones isolated from HeLa cells treated with toxic concentrations of a methylating carcinogen showed increased resistance to the cytotoxicity of N-methyl-N-nitrosourea. D₃₇ values were 6- to 100-fold higher than in the parental cell population. The absence of detectable levels of the repair enzyme O⁶-methylguanine-DNA methyltransferase indicated that the resistant clones were able to tolerate the presence of O⁶-methylguanine in their DNA. Analysis of N-methyl-N-nitrosourea survival in the hybrids between tolerant clones and HeLa cells showed that tolerance can be either recessive or codominant. Fusion between tolerant clones indicated two complementation groups. We measured spontaneous mutation rates at microsatellites and at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus in several tolerant clones. All the clones of Complementation Group I showed unstable microsatellites and 4-8-fold increases in mutation rates at hprt. No significant alterations in spontaneous mutation rates were found in clones of Complementation Group II. The data indicate that tolerance to methylation damage can be conferred by alterations in at least two different gene products and that one of the two groups has the mutator phenotype typical of mismatch correction defective cells.

¹ This work was partially supported by the Consiglio Nazionale delle Ricerche (CNR-Applicazioni Cliniche Ricerca Oncologica). S. C. is a recipient of an Istituto Superiore di Sanita' fellowship.

² To whom requests for reprints should be addressed.

Received 12/20/94. Accepted 5/ 5/95.

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