Nijmegen Breakage Syndrome (NBS) is a very rare autosomal recessive chromos
omal instability disorder characterized by microcephaly, growth retardation
, immunodeficiency and a high incidence of malignancies. Cells from NBS pat
ients are hypersensitive to ionizing radiation (IR) and display radioresist
ant DNA synthesis (RDS). NBS is caused by mutations in the NBS1 gene on chr
omosome 8q21 encoding a protein called nibrin. This protein is a component
of the hMre11/hRad50 protein complex, suggesting a defect in DNA double-str
and break (DSB) repair and/or cell cycle checkpoint function in NBS cells.
We established SV40 transformed, immortal NBS fibroblasts, from primary cel
ls derived from a Polish patient, carrying the common founder mutation 657d
el5, Immortalized NBS cells, like primary cells, are X-ray sensitive (2-fol
d) and display RDS following IR. They show an increased sensitivity to bleo
mycin (3.5-fold), etoposide (2.5-fold), camptothecin (3-fold) and mitomycin
C (1.5-fold), but normal sensitivity towards UV-C, Despite the clear hyper
sensitivity towards DSB-inducing agents, the overall rates of DSB-rejoining
in NBS cells as measured by pulsed field gel electrophoresis were found to
be very similar to those of wild type cells. This indicates that the X-ray
sensitivity of NBS cells is not directly caused by an overt defect in DSB
repair. (C) 1999 Elsevier Science B.V. AU rights reserved.