ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway

The rare diseases ataxia-telangiectasia (AT), caused by mutations in the ATM gene, and Nijmegen breakage syndrome (NBS), with mutations in the p95/nbs1 gene, share a variety of phenotypic abnormalities such as chromosomal instability, radiation sensitivity and defects in cell-cycle checkpoints in response to ionizing radiation(1-4). The ATM gene encodes a protein kinase that is activated by ionizing radiation or radiomimetic drugs(5,6), whereas p95/nbs1 is part of a protein complex that is involved in responses to DNA double-strand breaks(3,7). Here, because of the similarities between AT and NBS, we evaluated the functional interactions between ATM and p95/nbs1. Activation of the ATM kinase by ionizing radiation and induction of ATM-dependent responses in NBS cells indicated that p95/nbs1 may not be required for signalling to ATM after ionizing radiation. However, p95/nbs1 was phosphorylated on serine 343 in an ATM-dependent manner in vitro and in vivo after ionizing radiation. A p95/nbs1 construct mutated at the ATM phosphorylation site abrogated an S-phase checkpoint induced by ionizing radiation in normal cells and failed to compensate for this functional deficiency in NBS cells. These observations link ATM and p95/nbs1 in a common signalling pathway and provide an explanation for phenotypic similarities in these two diseases.
Publisher
MACMILLAN MAGAZINES LTD
Issue Date
2000-04
Language
ENG
Keywords

NIJMEGEN BREAKAGE SYNDROME; ATAXIA-TELANGIECTASIA; DNA-DAMAGE; IONIZING-RADIATION; PROTEIN-KINASE; REPAIR; P53; LINKAGE

Citation

NATURE, v.404, no.6778, pp.613 - 613

ISSN
0028-0836
URI
http://hdl.handle.net/10203/74814
Appears in Collection
BS-Journal Papers(저널논문)
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