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

Girard, P-M., Riballo, E., Begg, A., Waugh, A. and Jeggo, P. A. (2002) Nbs1 promotes ATM dependent phosphorylation events including those required for G1/S arrest. Oncogene, 21. pp. 4191-4199. ISSN 0950-9232

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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.

Item Type: Article
Depositing User: Gee Wheatley
Date Deposited: 11 Apr 2007
Last Modified: 16 Sep 2019 08:46
URI: http://sro.sussex.ac.uk/id/eprint/1055
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