An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele

Nijmegen breakage syndrome (NBS) is a rare chromosomal-instability syndrome associated with cancer predisposition, radiosensitivity and radioresistant DNA synthesis-S phase checkpoint deficiency, which results in the failure to suppress DNA replication origins following DNA damage. Approximately 90% of NBS patients are homozygous for the 657del5 allele(1,2), a truncating m utation of NBS1 that causes premature termination at codon 219. Because nul l mutations in MRE11 and RAD50, which encode binding partners of NBS1, are lethal in vertebrates(3-5), and mouse Nbs1-null mutants are inviable(6), we tested the hypothesis that the NBS1 657del5 mutation was a hypomorphic def ect. We showed that NBS cells contain the predicted 26-kD amino-terminal pr otein fragment, NBS1(p26) and a 70-kD NBS1 protein (NBS1(p70)) lacking the native N terminus. The NBSp26 protein is not physically associated with the MRE11 complex, whereas the p70 species is physically associated with it. N BS1(p70) is produced by internal translation initiation within the NBS1 mRN A using an open reading frame generated by the 657del5 frameshift. We propo se that the common NBS1 allele encodes a partially functional protein that diminishes the severity of the NBS phenotype.