DF/HCC Program AffiliationCancer Cell Biology
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.
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