THE MOLECULAR MECHANISM UNDERLYING FORMATION OF DELETIONS IN FANCONI-ANEMIA CELLS MAY INVOLVE A SITE-SPECIFIC RECOMBINATION

Spontaneous and induced chromosomal breakage is an important cellular feature of Fanconi anemia (FA), an inherited DNA repair disorder chara cterized by progressive bone marrow failure, developmental abnormaliti es, and predisposition to leukemia. We have previously reported that i n comparison to normal cells, there is a substantial increase in frequ ency of intragenic deletions at an endogenous locus (HPRT) in FA lymph oblasts. Taken together with the increased chromosomal instability, th ese observations indicated that the wild-type FA gene(s) plays an Impo rtant role in the maintenance of the genomic integrity. To obtain info rmation on the mechanism(s) underlying the genomic rearrangements in F A, the breakpoint sites of deletions in 11 FA-derived HPRT(-) mutants were analyzed. The results indicate that a significant proportion of d eletions involving a loss of a given exon are identical and that two d eletions of different size have the same 3' breakpoint. Interestingly, it appears that in most of the mutants there is a common deletion sig nal sequence, which suggests that the mutations in the FA gene(s) may lead to an aberrant site-specific cleavage activity that might be resp onsible for the deletion proneness and the chromosomal instability cha racteristic of the FA pathology. From the similarity or even identity of the signal sequence at some of the breakpoints with the consensus h eptamer which directs cleavage and joining in the assembly of immunogl obulin and T-cell receptor genes, we speculate that steps in common wi th the V(D)J recombinational process may be illegitimately involved in FA cells.