The relationship between radiation-induced G(1) arrest and chromosome aberrations in Li-Fraumeni fibroblasts with or without germline TP53 mutations

We previously showed that cultured fibroblasts from patients with the cance r-prone Li-Fraumeni (LF) syndrome, having heterozygous germline TP53 mutati ons, sustain less ionizing radiation-induced permanent G(1) arrest than nor mal fibroblasts. In contrast, fibroblast strains from LF patients without T P53 mutations showed normal G(1) arrest. We have now investigated the relat ionship between the extent of G(1) arrest and the level of structural chrom osome damage (mainly dicentrics, rings and acentric fragments) in cells at their first mitosis after G(1) irradiation, in 9 LF strains with TP53 mutat ions, 6 without TP53 mutations and 7 normal strains. Average levels of dama ge in the mutant strains were 50% higher than in normals, whereas in non-mu tant LF strains they were 100% higher. DNA double strand breaks (dsb) are k nown to act as a signal for p53-dependent G(1) arrest and to be the lesions from which chromosome aberrations arise. These results suggest that a mini mal level of dsb is required before the signal for arrest is activated and that p53-defective cells have a higher signal threshold than p53-proficient cells. Dsb that do not cause G(1) blockage can progress to mitosis and app ear as simple deletions or interact to form exchange aberrations. The eleva ted levels in the non-mutant strains may arise from defects in the extent o r accuracy of dsb repair. In LF cells with or without TP53 mutations, the r educed capacity to eliminate or repair chromosomal damage of the type induc ed by ionising radiation, may contribute to cancer predisposition in this s yndrome. (C) 2001 Cancer Research Campaign.