Chromosomal sensitivity to clastogenic agents and cell cycle perturbations in Nijmegen Breakage Syndrome lymphoblastoid cell lines

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Abstract
The relationship between chromosomal breakage and perturbations of cell cycle progression was investigated in lymphoblastoid cell lines established from a healthy donor, two subjects affected by Nijmegen Breakage Syndrome NBS and an ataxia-telangiectasia AT patient. The cytogenetic analysis revealed a similar chromosomal hypersensitivity in both NBS and AT cells exposed in the G1 phase to 200 cGy Xrays or in G2 to 15-30 cGy. Similarly, no differences were observed in the frequency of chromatid-type aberrations induced in G2 by 1-2 pg ml calicheamicin c1, a DNA double-strand break inducer. In addition, as observed in AT cells, the rate of G2 radiation-induced chromosomal damage was less enhanced in NBS than in control cells following 3-h incubation with inhibitors of DNA synthesis repair cytosine arabinoside, aphidicolin, DMSO, hydroxyurea, caffeine. This is suggestive of an altered DNA lesion-processing pathway common to both syndromes. Despite the close resemblance of cellular phenotypes in the two syndromes, the analysis of mitotic indices carried out at 2 and 4 h postirradiation indicated that NBS sustained a G2-delay greater than that observed in AT cells. Furthermore, the flow cytometric analysis of 50-300 cGy irradiated cells at 10 and 20 h before harvesting showed that NBS cells sustained a G2 M phase arrest markedly lower than AT cells. Our data indicate that NBS and AT gene products are involved in a common pathway of radiation-induced chromosomal damage, but in a different one for cell cycle control after irradiation.

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