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

Nature Genetics volume 27, pages 417–421 (2001)Cite this article

Abstract

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 allele1,2, a truncating mutation of NBS1 that causes premature termination at codon 219. Because null mutations in MRE11 and RAD50, which encode binding partners of NBS1, are lethal in vertebrates3,4,5, and mouse Nbs1-null mutants are inviable6, we tested the hypothesis that the NBS1 657del5 mutation was a hypomorphic defect. We showed that NBS cells contain the predicted 26-kD amino-terminal protein fragment, NBS1p26, and a 70-kD NBS1 protein (NBS1p70) 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. NBS1p70 is produced by internal translation initiation within the NBS1 mRNA using an open reading frame generated by the 657del5 frameshift. We propose that the common NBS1 allele encodes a partially functional protein that diminishes the severity of the NBS phenotype.

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Figure 1: NBS 657del5 LCLs express variant NBS1 protein.
Figure 2: Structure of NBS1p70.
Figure 3: Subcellular localization of the MRE11 complex in NBS cells.
Figure 4: Production of NBS1p70 from NBS1 657del5 cDNA.
Figure 5: NBS1p70 is specific to NBS 657del5 cells.

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Acknowledgements

We thank P. Maraschio, R. Varon and B. Sugden for cell lines; P. Farnham for pcDNA3 and the luciferase cDNA; T. de Lange for TRF2 antiserum; E. Zegna, J. Wells and members of the Petrini laboratory for comments and helpful discussions. This work was supported by grants from the Milwaukee Foundation, the National Institutes of Health GM59413 and the D.O.E. ER62859.

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  1. Laboratory of Genetics, University of Wisconsin Medical School, Madison, Wisconsin, USA

    Richard S. Maser, Robert Zinkel & John H.J. Petrini

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  1. Richard S. Maser
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Correspondence to John H.J. Petrini.

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Maser, R., Zinkel, R. & Petrini, J. An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele. Nat Genet 27, 417–421 (2001). https://doi.org/10.1038/86920

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