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

The molecular spectra of mutations photoinduced (405 nm) by 4,5',8-tri methylpsoralen monoadducts (MA), at an endogenous locus, hypoxanthine- guanine phosphoribosyltransferase (HPRT) in normal and in a Fanconi an emia (FA) lymphoblast cell line, complementation group D, are presente d. We show that, in normal cells, MA induce only base substitutions. I n 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 an d normal cell lines. The majority of base substitutions are located at sites of psoralen MA which suggest that 4,5',8-trimethylpsoralen phot oinduced mutations are targeted and preferentially formed in the non-t ranscribed strand. Moreover, point mutations induced by MA in normal a nd FA cells are not homogeneously distributed, they preferentially occ ur in exon 8 of the HPRT gene. This heterogeneous distribution of muta tions is ascribed to processing of MA. Great similarities were found b etween normal and FA cells with respect to the nature and location of point mutation at the HPRT gene; the high proneness to deletions remai ns one of the major instability features of FA.