Research Abstract

Work in the laboratory is focussed on examining the role of the ATM protein kinase in regulating DNA repair. ATM is the gene mutated in the hereditary disorder Ataxia Telangiectasia (AT). Patients with AT exhibit neurological dysfunction, increased incidence of cancer and extreme sensitivity to DNA damage. We have identified the Tip60 Histone acetyltransferase (HAT) as a key upstream regulator of ATM. Tip60 associates with the FATC domain of ATM. Activation of ATM by DNA damage is driven by the Tip60-dependent acetylation of the ATM protein. This acetylation of ATM activates the kinase activity of the ATM protein, resulting in phosphorylation of key down stream target proteins and the co-ordinate repair of DNA. Current experiments are focussed on understanding how histone modifications at sites of DNA damage mediate activation of the ATM-Tip60 complex. In addition, we are identifying inhibitors of Tip60 as potential chemo- and radio-sensitizers, and identifiying Tip60 mutations in human tumors.

Publications

• Roy K, Wang L, Makrigiorgos GM, Price BD.Methylation of the ATM promoter in glioma cells alters ionizing radiation sensitivity.Biochem Biophys Res Commun 2006 Jun 9;344(3):821-6.
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• Jiang X, Sun Y, Chen S, Roy K, Price BD.The FATC domains of PIKK proteins are functionally equivalent and participate in the Tip60-dependent activation of DNA-PKcs and ATM.J Biol Chem 2006 Jun 9;281(23):15741-6.
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• Sun Y, Jiang X, Chen S, Fernandes N, Price BD.A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM.Proc Natl Acad Sci U S A 2005 Sep 13;102(37):13182-7.
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• Fernandes N, Sun Y, Chen S, Paul P, Shaw RJ, Cantley LC, Price BD.DNA damage-induced association of ATM with its target proteins requires a protein interaction domain in the N terminus of ATM.J Biol Chem 2005 Apr 15;280(15):15158-64.
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• Makrigiorgos GM, Chakrabarti S, Zhang Y, Kaur M, Price BD.A PCR-based amplification method retaining the quantitative difference between two complex genomes.Nat Biotechnol 2002 Sep;20(9):936-9.
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