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Molecular and Cellular Biology, December 2007, p. 8502-8509, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.01382-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

DNA Damage-Induced Acetylation of Lysine 3016 of ATM Activates ATM Kinase Activity{triangledown} ,{dagger}

Yingli Sun, Ye Xu, Kanaklata Roy, and Brendan D. Price*

Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115

Received 1 August 2007/ Returned for modification 25 August 2007/ Accepted 25 September 2007

The ATM protein kinase is essential for cells to repair and survive genotoxic events. The activation of ATM's kinase activity involves acetylation of ATM by the Tip60 histone acetyltransferase. In this study, systematic mutagenesis of lysine residues was used to identify regulatory ATM acetylation sites. The results identify a single acetylation site at lysine 3016, which is located in the highly conserved C-terminal FATC domain adjacent to the kinase domain. Antibodies specific for acetyl-lysine 3016 demonstrate rapid (within 5 min) in vivo acetylation of ATM following exposure to bleomycin. Furthermore, lysine 3016 of ATM is a substrate in vitro for the Tip60 histone acetyltransferase. Mutation of lysine 3016 does not affect unstimulated ATM kinase activity but does abolish upregulation of ATM's kinase activity by DNA damage, inhibits the conversion of inactive ATM dimers to active ATM monomers, and prevents the ATM-dependent phosphorylation of the p53 and chk2 proteins. These results are consistent with a model in which acetylation of lysine 3016 in the FATC domain of ATM activates the kinase activity of ATM. The acetylation of ATM on lysine 3016 by Tip60 is therefore a key step linking the detection of DNA damage and the activation of ATM kinase activity.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, JF516, 44 Binney St., Boston, MA 02115. Phone: (617) 632-4946. Fax: (617) 632-4599. E-mail: brendan_price{at}dfci.harvard.edu

{triangledown} Published ahead of print on 8 October 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2007, p. 8502-8509, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.01382-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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