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 cancer-prone Li-Fraumeni (LF) syndrome, having heterozygous germline TP53 mutations, sustain less ionizing radiation-induced permanent G(1)arrest than normal fibroblasts. In contrast, fibroblast strains from LF patients without TP53 mutations showed normal G(1)arrest. We have now investigated the relationship between the extent of G(1)arrest and the level of structural chromosome damage (mainly dicentrics, rings and acentric fragments) in cells at their first mitosis after G(1)irradiation, in 9 LF strains with TP53 mutations, 6 without TP53 mutations and 7 normal strains. Average levels of damage in the mutant strains were 50% higher than in normals, whereas in non-mutant LF strains they were 100% higher. DNA double strand breaks (dsb) are known 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 minimal 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 appear as simple deletions or interact to form exchange aberrations. The elevated levels in the non-mutant strains may arise from defects in the extent or accuracy of dsb repair. In LF cells with or without TP53 mutations, the reduced capacity to eliminate or repair chromosomal damage of the type induced by ionising radiation, may contribute to cancer predisposition in this syndrome.
Boyle
J M
JM
CRC Department of Cancer Genetics, Paterson Institute for Cancer Research, CRC Christie Research Centre, Manchester, UK.
Spreadborough
A
A
Greaves
M J
MJ
Birch
J M
JM
Varley
J M
JM
Scott
D
D
D002869:Chromosome Aberrations; D016193:G1 Phase / Q000528:radiation effects*; D016158:Genes, p53; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics* / Q000473:pathology