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A more recent version of this article appeared on June 9, 2006
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281/23/15741    most recent
M513172200v1
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Papers In Press, published online ahead of print April 9, 2006
J. Biol. Chem, 10.1074/jbc.M513172200
Submitted on December 9, 2005
Accepted on April 9, 2006

The FATC domains of PIKK proteins are functionally equivalent and participate in the Tip60-dependent activation of DNA-PKcs and ATM

Xiaofeng Jiang, Yingli Sun, Shujuan Chen, Kanaklata Roy, and Brendan D. Price

Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115

Corresponding Author: brendan_price{at}dfci.harvard.edu

Members of the PIKK family, including the ATM, DNA-PKcs, Atr and Trrap proteins, function in signal transduction pathways which activate the DNA damage response. PIKK proteins contain a conserved c-terminal FAT/kinase-domain/FATC domain structure. The FATC domain of ATM mediates the interaction between ATM and Tip60, a histone acetyltransferase which regulates activation of ATM. Here, we examined if the FATC domains of DNA-PKcs, Atr and Trrap were also able to interact with Tip60. Deletion of ATM’s FATC domain blocked the interaction between ATM and Tip60 and suppressed the activation of ATM’s kinase activity by DNA damage. Replacement of ATM’s FATC domain with the FATC domains of either DNA-PKcs, Atr or Trrap restored the activation of ATM and its association with Tip60. These results indicate that the FATC domains of DNA-PKcs, Atr, Trrap and ATM are functionally equivalent. Immunoprecipitation experiments demonstrated that Tip60 is constitutively associated with DNA-PKcs, and that the HAT activity associated with DNA-PKcs is upregulated by DNA damage. When Tip60 expression was suppressed by siRNA, the activation of DNA-PKcs (measured by autophosphorylation of DNA-PKcs at serine 2056 and threonine 2609) was inhibited, demonstrating a key role for Tip60 in the activation of DNA-PKcs by DNA damage. The conserved FATC domain of PIKK proteins may therefore function as a binding domain for the Tip60 HAT. Further, the ability of Tip60 to regulate the activation of both ATM and DNA-PKcs in response to DNA damage demonstrates that Tip60 is a key component of the DNA damage signaling network.


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