The hypoxanthine guanine phosphoribosyltransferase (HPRT) gene is mutated by a variety of genotoxic agents in adult rat liver (ARL) epithelial cell lines. By polymerase chain reaction (PCR) amplification and DNA sequencing of rat ARL cell HPRT gene sequences with mouse- and rat-specific oligonucleotides, a large portion of the rat HPRT transcriptional promoter region was sequenced. This region exhibits approximately 60% homology with the corresponding mouse sequence, contains a similar G/C-rich region at its 3' end, and contains a similar series of 6-nucleotide (nt) GGGCGG repeats. To determine if this region is a target for mutation by different genotoxins, HPRT-deficient ARL mutants induced by 2-acetylaminofluorene (AAF), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), or 7,12-dimethyl-benz[a]anthracene (DMBA) were isolated and studied. A 1003-nt fragment of predominantly HPRT regulatory sequences was amplified by PCR using purified genomic DNA from 17 independent mutants and sequenced directly. None of the 17 mutants examined exhibited any alterations in the transcriptional regulatory region or the 5' untranslated region of HPRT exon 1 after direct sequencing analysis of PCR products. In addition, none of the 2-AAF-induced mutants exhibited differences in in vitro transcription rates as determined by nuclear run-on analysis. These data suggest that regulatory sequences of the HPRT gene are not a primary target for mutation by the genotoxins studied.
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