HPRT gene expression differs in mutants derived from normal and Fanconi anemia cells: Analysis of spontaneous and psoralen-photoinduced mutants

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Abstract
Fanconi anemia (FA) is an autosomal recessive disorder characterized by chromosomal instability and abnormalities in the processing of DNA lesions induced by cross-linking agents. We previously reported that after photoaddition of psoralen derivatives the frequency ofHPRT − mutants was significantly lower in FA than in normal human lymphoblasts. The hypomutability in FA cells was shown to be associated with an increased deletion frequency at theHPRT gene level. Further characterization of 70 unrearranged mutants (without detectable changes in restriction enzyme fragment length) according to theHPRT gene expression is reported here. Northern blot hybridization analysis demonstrates considerable differences in mRNA phenotyping between normal and FA cells. In normal cells, the minority of spontaneous (31%) and psoralen-induced mutants (0% and 14% according to treatment) arise from mutations that alter theHPRT gene transcription. In contrast to normal cells, in the majority of mutants isolated from FA cells,HPRT gene expression is found to be affected. Indeed a large proportion of either spontaneous (67%) or psoralen-induced (56% and 46%) mutants did not produce detectable amounts of mRNA. These results suggest that the mutagenic processing of spontaneous and psoralen-photoinduced lesions differs in normal and FA cells.