THE FIDELITY OF DOUBLE-STRAND BREAKS PROCESSING IS IMPAIRED IN COMPLEMENTATION GROUP-B AND GROUP-D OF FANCONI-ANEMIA, A GENETIC INSTABILITYSYNDROME

In mammalian cells, nonhomologous end-joining is the predominant mecha nism to eliminate DNA double strand breaks, Such events are at the ori gin of deletion mutagenesis and chromosomal rearrangements, The hallma rk of Fanconi anemia, an inherited cancer prone disorder; is increased chromosomal breakage associated to over-production of deletions. Know ing that double strand breaks are at the origin of deletion mutagenesi s, the question arises whether their processing is affected in FA, We set up a ''host cell end-joining assay'' to analyze the fate of double strand breaks into extrachromosomal substrates transiently replicated in normal and FA-D lymphoblasts. Although no difference in plasmid su rvival was found, blunt-ended breaks were sealed with significantly, l ower fidelity in FA cells, resulting in a higher deletion frequency an d a larger deletion size. The results suggest that FA-D and FA-B gene products are likely to play a role in end-joining fidelity, of specifi c DNA double strand breaks.