Expression of full-length NBS1 protein restores normal radiation responses in cells from Nijmegen breakage syndrome patients.

ABSTRACT

Cells from Nijmegen breakage syndrome (NBS) display multiple phenotypes, such as chromosomal instability, hypersensitivity to cell killing from ionizing radiation, and possibly abnormal cell cycle checkpoints. NBS1, a gene mutated in NBS patients, appears to encode a possible repair protein, which could form the foci of a sensor-like molecular complex capable of detecting DNA double strand breaks, however, it has no kinase domain for signaling DNA damage. Here, we report that the stable expression of NBS1 cDNA in NBS cells after transfection results in the complete restoration of foci formation in the nucleus, and in normal cell survival after irradiation. The prolonged G2 block observed after irradiation was also abolished by expression of NBS1, providing additional confirmation that the G2 checkpoint is abrogated in NBS cells. These results suggest that a defective NBS1 protein could be the sole cause of the NBS phenotype, and that NBS1 likely interacts with another protein(s) to produce the entire range of NBS phenotypic expression.