Cell and Tissue Signaling

Tuesday, October 18, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP269) Tip60 Histone Acetyltransferase regulates the acetyaltion and activation of ATM following DNA damage.

Sun, Yingli*,1, Price, Brendan1, 1 Radiation Oncology, Boston, MA, USA

ABSTRACT- The ATM protein kinase is essential for the accurate and timely repair of DNA strand breaks. ATM activation may involve the MRN complex or changes in chromatin structure. However, the signal transduction pathway linking DNA strand breaks to activation of ATMs kinase activity is not clearly defined. Here, we demonstrate that DNA damage induces the rapid acetylation of ATM. This acetylation is dependent on the Tip60 Histone Acetyltranferase (HAT). Suppression of Tip60 blocks the activation of ATMs kinase activity and prevents the ATM-dependent phosphorylation of p53 and chk2. Further, inactivation of Tip60 sensitizes cells to ionizing radiation. ATM forms a stable complex with Tip60 through the conserved FATC domain of ATM. Mutation or deletion of the FATC domain blocks both ATM acetylation and activation of ATMs kinase activity. Further, the FATC domains of Atr, DNA-PKcs and TRRAP can be substituted for the FATC domain of ATM. The FATC domains of ATM, Atr, DNA-PKcs and TRRAP are therefore functionally equivalent. The association of Tip60 with ATM is constitutive, and is not regulated in response to DNA damage. Instead, the HAT activity of the ATM-Tip60 complex is specifically activated by DNA damage. We propose that the activation of ATM by DNA damage requires Tip60 dependent acetylation of ATM. These results provide a mechanistic framework to explain how changes in chromatin structure during DNA repair are communicated to the ATM protein kinase.

Key words: ATM, Tip60, acetylation

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2005 RRS