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Activation of ATM by DNA Damaging Agents

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Annual summary 1 Sep 2003-31 Aug 2004

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Ataxia-telangiectasia mutated ATM is a serinethreonine protein kinase that acts as a master switch controlling the cell cycle in response to ionizing radiation-induced DNA double-strand breaks DSBs. Carriers of ATM mutations are at increased risk for breast cancer. Since many anti-tumor chemotherapeutics used in breast cancer treatment have the capacity to induce DNA DSBs, I have investigated the requirement for ATM in the cellular response to these agents. I have previously identified doxorubicin as an agent that stimulates ATM autophosphorylation and the ATM-dependent phosphorylation of p53. I have now expanded these studies to examine numerous downstream effectors of ATM and, in all cases, observe a depend on ATM for phosphorylation. These phosphorylation events are attenuated by pretreatment of cells with N-acetyl cysteine, suggesting a role for hydroxyl radicals in these vents. My studies have now been expanded and I have observed doxorubicin-induced phosphorylation of a subset of downstream effectors of ATM in two human breast cancer cell lines. Studies are now underway to identify proteins that interact with ATM following drug treatment. Characterization of a role for ATM in the cellular response to anti-tumor chemotherapeutics could have significant implications for the treatment of breast cancer patients harboring mutations in ATM.

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  • Biochemistry
  • Anatomy and Physiology
  • Medicine and Medical Research

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