MUTAGENIC PROCESSING OF PSORALEN MONOADDUCTS DIFFER IN NORMAL AND FANCONI-ANEMIA CELLS

The molecular spectra of mutations photoinduced (405 nm) by 4,5',8-trimethylpsoralen monoadducts (MA), at an endogenous locus, hypoxanthine-guanine phosphoribosyltransferase (HPRT) in normal and in a Fanconi anemia (FA) lymphoblast cell line, complementation group D, are presented. We show that, in normal cells, MA induce only base substitutions. In contrast, in FA cells which are partially deficient in the incision of MA, deletions are preferentially induced over point mutations (62% of the total). Although the proportion of base substitutions is lower in FA cells, their type and sequence distribution are similar in FA and normal cell lines. The majority of base substitutions are located at sites of psoralen MA which suggest that 4,5',8-trimethylpsoralen photoinduced mutations are targeted and preferentially formed in the non-transcribed strand. Moreover, point mutations induced by MA in normal and FA cells are not homogeneously distributed, they preferentially occur in exon 8 of the HPRT gene. This heterogeneous distribution of mutations is ascribed to processing of MA. Great similarities were found between normal and FA cells with respect to the nature and location of point mutation at the HPRT gene; the high proneness to deletions remains one of the major instability features of FA.