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A new effector pathway links ATM kinase with the DNA damage response

Nature Cell Biology volume 6, pages 968–976 (2004)Cite this article

Abstract

The related kinases ATM (ataxia-telangiectasia mutated) and ATR (ataxia-telangiectasia and Rad3-related) phosphorylate a limited number of downstream protein targets in response to DNA damage. Here we report a new pathway in which ATM kinase signals the DNA damage response by targeting the transcriptional cofactor Strap. ATM phosphorylates Strap at a serine residue, stabilizing nuclear Strap and facilitating formation of a stress-responsive co-activator complex. Strap activity enhances p53 acetylation, and augments the response to DNA damage. Strap remains localized in the cytoplasm in cells derived from ataxia telangiectasia individuals with defective ATM, as well as in cells expressing a Strap mutant that cannot be phosphorylated by ATM. Targeting Strap to the nucleus reinstates protein stabilization and activates the DNA damage response. These results indicate that the nuclear accumulation of Strap is a critical regulator in the damage response, and argue that this function can be assigned to ATM through the DNA damage-dependent phosphorylation of Strap.

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Figure 1: DNA damage induces phosphorylation of Strap.
Figure 2: Intracellular localization of Strap and StrapS203A.
Figure 3: Strap localization in ataxia telangiectasia cells.
Figure 4: Strap Ser 203 regulates the interaction between Strap and p300 and the acetylation of p53.
Figure 5: Ser 203 is required for the p53 response.
Figure 6: Nuclear Strap undergoes DNA damage-dependent protein stabilization.
Figure 7: Nuclear Strap activates the DNA damage response.

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Acknowledgements

We thank M. Caldwell for assistance in preparing the manuscript. This work was supported by the Medical Research Council, the Leukaemia Research Fund, Cancer Research UK and the European Union. We thank M. B. Kastan for the wild-type and kinase-dead ATM expression vectors.

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  1. Constantinos Demonacos & Marija Krstic-Demonacos

    Present address: School of Pharmacy and Pharmaceutical Sciences (C.D.), School of Biological Sciences (M.K-D.), University of Manchester, Manchester, M13 9PT, UK

Authors and Affiliations

  1. Division of Biochemistry and Molecular Biology, Davidson Building, University of Glasgow, Glasgow, G12 8QQ, UK

    Constantinos Demonacos, Marija Krstic-Demonacos, Linda Smith, Danmei Xu, Darran P. O'Connor, Martin Jansson & Nicholas B. La Thangue

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Fig. S1, Fig. S2, Fig. S3, Fig. S4 (PDF 576 kb)

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Demonacos, C., Krstic-Demonacos, M., Smith, L. et al. A new effector pathway links ATM kinase with the DNA damage response. Nat Cell Biol 6, 968–976 (2004). https://doi.org/10.1038/ncb1170

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