Hypersensitivity to ionizing radiation, in vitro, in a new chromosomal breakage disorder, the Nijmegen Breakage syndrome

Taalman, R. D. F. M.; Jaspers, N.G.J.; Scheres, J. M. J. C.; Wit, Jan de; Hustinx, T. W. J.

doi:10.1016/0167-8817(83)90021-4

Cited by 83 publications

(52 citation statements)

References 24 publications

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“…It is difficult, however, to accept this hypothesis, as cells from NBS patients are far more sensitive per unit of radiation when treated in G2 than in Go/G1 phase of cell cycle. 37 To our knowledge, no data are available in the literature on the amount of nibrin in NBS heterozygotes. Our densitometric analysis after immunoblotting indicates only a slight reduction in some of the LCLs from NBS carriers (Figure 2), and, at the present time, the significance of these results cannot be clarified.…”

Section: Discussionmentioning

confidence: 99%

Chromosome instability and nibrin protein variants in NBS heterozygotes

et al. 2003

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The frequency of spontaneous chromosome abnormalities in peripheral blood lymphocytes and the X-ray G2 sensitivity in lymphoblastoid cell lines (LCL) have been evaluated in heterozygous subjects from three unrelated Nijmegen Breakage Syndrome (NBS) families, characterised by different mutations in the NBS1 gene. In all the 13 NBS heterozygotes analysed, we found spontaneous chromosome instability consisting in chromosome and chromatid breakages and rearrangements, while radiosensitivity was similar to that of control LCLs in seven out of eight tested NBS heterozygotes. The densitometric analysis of nibrin by immunoblotting indicated only a slight reduction in some of the LCLs from NBS carriers, whereas the immunoprecipitation assay appears a more reliable tool to detect NBS carriers. By means of immunoprecipitation, we investigated two homozygous and four heterozygous subjects. In the cells of the NBS patient 668, with the mutation 900del25, an alternative form of nibrin with a molecular weight of approximately 55 kDa has been detected. This variant protein, together with the normal p95, was also found in the LCL 34 established from a carrier of the same family. Signals of nibrin with a molecular weight lower than 95 kDa, but higher than that observed in LCLs 668 and 34, were detected also in three carriers from the family with mutation 835del4.

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Section: Discussionmentioning

confidence: 99%

Chromosome instability and nibrin protein variants in NBS heterozygotes

et al. 2003

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“…The MRN complex is composed of Mre11, Rad50 and Nbs1 proteins, which are involved in DNA repair by homologous recombination and nonhomologous end-joining. This complex is crucial for maintaining genomic integrity, illustrated by the fact that the cancer-prone syndromes ataxia-telangiectasialike disorder (ATLD) and Nijmegen Breakage Syndrome (NBS) result from a lack of functional Mre11 and Nbs1, respectively (Taalman et al, 1983;Maser et al, 1997;Shiloh, 1997;Carney et al, 1998;Stewart et al, 1999;D'Amours and Jackson, 2002) Loss of 53BP1 results in a defect in checkpoint activation in S phase and G2/M (DiTullio et al, 2002;Fernandez-Capetillo et al, 2002;Wang et al, 2002). Phosphorylation of histone H2AX (gH2AX) occurs following a doublestrand break and is a sensitive marker for DNA damage (Rogakou et al, 1998;Paull et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

E2F1 induces MRN foci formation and a cell cycle checkpoint response in human fibroblasts

et al. 2006

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Deregulation of the Rb/E2F pathway in human fibroblasts results in an E2F1-mediated apoptosis dependent on Atm, Nbs1, Chk2 and p53. Here, we show that E2F1 expression results in MRN foci formation, which is independent of the Nbs1 interacting region and the DNA-binding domain of E2F1. E2F1-induced MRN foci are similar to irradiation-induced foci (IRIF) that result from doublestrand DNA breaks because they correlate with 53BP1 and cH2AX foci, do not form in NBS cells, do form in AT cells and do not correlate with cell cycle entry. In fact, we find that in human fibroblasts deregulated E2F1 causes a G1 arrest, blocking serum-induced cell cycle progression, in part through an Nbs1/53BP1/p53/p21 WAF1/CIP1 checkpoint pathway. This checkpoint protects against apoptosis because depletion of 53BP1 or p21 WAF1/CIP1 increases both the rate and extent of apoptosis. Nbs1 and p53 contribute to both checkpoint and apoptosis pathways. These results suggest that E2F1-induced foci generate a cell cycle checkpoint that, with sustained E2F1 activity, eventually yields to apoptosis. Uncontrolled proliferation due to Rb/E2F deregulation as well as inactivation of both checkpoint and apoptosis programs would then be required for transformation of normal cells to tumor cells.

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“…Aile ve bakıcılar, lenfoma ve diğer malignitelerin belirtileri hakkında bilgilendirilmelidir. Bu hastalarda kromozomal instabilite nedeniyle radyoterapiden özellikle kaçınılmalıdır (17). Mevcut immün yetmezlik tablosuna göre, ağır kombine immün yetmezlik hastalarında olduğu gibi canlı aşıların yaptırılmaması sağlanmalı, uygun antibakteriyel ve antifunfal profilaksi, gerekirse IVIG replasman tedavisi başlanmalıdır.…”

Section: Discussionunclassified