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Nbs1 promotes ATM dependent phosphorylation events including those required for G1/S arrest

Oncogene volume 21, pages 4191–4199 (2002)Cite this article

Abstract

Cell lines from Nijmegen Breakage Syndrome (NBS) and ataxia telangiectasia (A-T) patients show defective S phase checkpoint arrest. In contrast, only A-T but not NBS cells are significantly defective in radiation-induced G1/S arrest. Phosphorylation of some ATM substrates has been shown to occur in NBS cells. It has, therefore, been concluded that Nbs1 checkpoint function is S phase specific. Here, we have compared NBS with A-T cell lines (AT-5762ins137) that express a low level of normal ATM protein to evaluate the impact of residual Nbs1 function in NBS cells. The radiation-induced cell cycle response of these NBS and ‘leaky’ A-T cells is almost identical; normal G2/M arrest after 2 Gy, intermediate G1/S arrest depending on the dose and an A-T-like S phase checkpoint defect. Thus, the checkpoint assays differ in their sensitivity to low ATM activity. Radiation-induced phosphorylation of the ATM-dependent substrates Chk2, RPAp34 and p53-Ser15 are similarly impaired in AT-5762ins137 and NBS cells in a dose dependent manner. In contrast, NBS cells show normal ability to activate ATM kinase following irradiation in vitro and in vivo. We propose that Nbs1 facilitates ATM-dependent phosphorylation of multiple downstream substrates, including those required for G1/S arrest.

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Acknowledgements

We thank Dr A Carr and AR Lehmann for help and support. Work contributing to this study was supported by grants from the Leukaemia Research Fund, the Industry-funded UKCCCR Radiation Research Programme, European Union grant FIGH CT 1999 00010 and an MRC ROPA award.

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Authors and Affiliations

  1. MRC Cell Mutation Unit, University of Sussex, Brighton, BN1 9RR, East Sussex, UK

    Pierre-Marie Girard, Enriqueta Riballo, Alastair Waugh & Penny A Jeggo

  2. Department of Experimental Therapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Plesmanlaan 21, Amsterdam, 1066, CX, The Netherlands

    Adrian C Begg

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  1. Pierre-Marie Girard
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  2. Enriqueta Riballo
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  3. Adrian C Begg
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  4. Alastair Waugh
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  5. Penny A Jeggo
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Correspondence to Penny A Jeggo.

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Girard, PM., Riballo, E., Begg, A. et al. Nbs1 promotes ATM dependent phosphorylation events including those required for G1/S arrest. Oncogene 21, 4191–4199 (2002). https://doi.org/10.1038/sj.onc.1205596

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