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The relationship between radiation-induced G1arrest and chromosome aberrations in Li-Fraumeni fibroblasts with or without germline TP53 mutations

By J M Boyle, A Spreadborough, M J Greaves, J M Birch, J M Varley and D Scott

Abstract

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 G1 arrest than normal fibroblasts. In contrast, fibroblast strains from LF patients without TP53 mutations showed normal G1 arrest. We have now investigated the relationship between the extent of G1 arrest and the level of structural chromosome damage (mainly dicentrics, rings and acentric fragments) in cells at their first mitosis after G1 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 G1 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 G1 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. © 2001 Cancer Research Campaign http://www.bjcancer.co

Topics: Regular Article
Publisher: Nature Publishing Group
OAI identifier: oai:pubmedcentral.nih.gov:2364041
Provided by: PubMed Central
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    Citations

    1. (1999). Heterozygous germline mutations in hCHK2 are a cause of Li-Fraumeni syndrome.
    2. (2000). Mechanisms of DNA double-strand break repair and their potential to induce chromosomal aberrations.

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