Involvement of novel autophosphorylation sites in ATM activation

Kozlov, Sergei V., Graham, Mark E., Peng, Cheng, Chen, Philip, Robinson, Phillip J. and Lavin, Martin F. (2006) Involvement of novel autophosphorylation sites in ATM activation. Embo Journal, 25 15: 3504-3514. doi:10.1038/sj.emboj.7601231


Author Kozlov, Sergei V.
Graham, Mark E.
Peng, Cheng
Chen, Philip
Robinson, Phillip J.
Lavin, Martin F.
Title Involvement of novel autophosphorylation sites in ATM activation
Journal name Embo Journal   Check publisher's open access policy
ISSN 0261-4189
Publication date 2006-08-09
Sub-type Article (original research)
DOI 10.1038/sj.emboj.7601231
Volume 25
Issue 15
Start page 3504
End page 3514
Total pages 11
Place of publication Oxford, U.K.
Publisher Nature Publishing Group
Collection year 2006
Language eng
Subject C1
320305 Medical Biochemistry - Proteins and Peptides
730108 Cancer and related disorders
1101 Medical Biochemistry and Metabolomics
Abstract ATM kinase plays a central role in signaling DNA double-strand breaks to cell cycle checkpoints and to the DNA repair machinery. Although the exact mechanism of ATM activation remains unknown, efficient activation requires the Mre11 complex, autophosphorylation on S1981 and the involvement of protein phosphatases and acetylases. We report here the identification of several additional phosphorylation sites on ATM in response to DNA damage, including autophosphorylation on pS367 and pS1893. ATM autophosphorylates all these sites in vitro in response to DNA damage. Antibodies against phosphoserine 1893 revealed rapid and persistent phosphorylation at this site after in vivo activation of ATM kinase by ionizing radiation, paralleling that observed for S1981 phosphorylation. Phosphorylation was dependent on functional ATM and on the Mre11 complex. All three autophosphorylation sites are physiologically important parts of the DNA damage response, as phosphorylation site mutants (S367A, S1893A and S1981A) were each defective in ATM signaling in vivo and each failed to correct radiosensitivity, genome instability and cell cycle checkpoint defects in ataxia-telangiectasia cells. We conclude that there are at least three functionally important radiation-induced autophosphorylation events in ATM.
Keyword Biochemistry & molecular Biology
Cell Biology
ATM
Autophosphorylation
DNA damage signaling
Phosphorylation sites mapping
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2007 Higher Education Research Data Collection
School of Medicine Publications
 
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Created: Wed, 15 Aug 2007, 20:07:36 EST