Understanding the molecular control of cellular responses to DNA damage has significance for both cancer development and cancer therapies. Among the most critical types of DNA damage with which our cells need to cope are breaks in the phosphodiester backbone. The ATM protein kinase is a central signaling molecule in modulating cellular responses to DNA breakage. In the previous funding period of this grant, significant progress was made in elucidating the mechanisms involved in the activation of the ATM kinase. In addition, we were able to identify specific protein targets of the ATM enzyme and to decipher the functional significance of these phosphorylation events. In this application, we build upon these successes and propose experiments that will further elucidate molecular mechanisms involved in cellular responses to DNA breakage and other types of DNA damage. We found that ATM exists in cells as a homodimer and is activated after DNA damage by an intermolecular autophosphorylation on serine 1981 that causes dissociation of the dimer. We recently identified an additional serine in the ATM protein that becomes phosphorylated in response to DNA damage. Experiments are proposed to explore the functional significance of this new post-translational modification. In particular, we expect that this phosphorylation event contribute to modulating the cellular activities of the ATM kinase after its initial activation. In addition, experiments are proposed that will explore the nature of ATM interactions with chromosomal proteins so that we can better understand how ATM associates with chromatin and senses alterations in higher order chromatin structures to become activated. The elucidation of the ATM activation mechanism also led to our ability to activate the enzyme in the absence of detectable DNA damage. This led to proof-of-principle experiments demonstrating that activation of the ATM-p53 pathway prior to irradiation leads to radioprotection of mice exposed to total body irradiation. Preliminary data is also presented demonstrating that activation of the ATM-p53 pathway can prevent cancer development in multiple mouse models, including cancers caused by ionizing irradiation, chemical carcinogens, or activated oncogenes. Experiments are proposed to further explore the molecular mechanisms involved in both the radioprotective effects and the cancer preventative effects of ATM activation.
| Goldstein, Michael; Kastan, Michael B (2015) Repair versus Checkpoint Functions of BRCA1 Are Differentially Regulated by Site of Chromatin Binding. Cancer Res 75:2699-707 |
| Goldstein, Michael; Derheimer, Frederick A; Tait-Mulder, Jacqueline et al. (2013) Nucleolin mediates nucleosome disruption critical for DNA double-strand break repair. Proc Natl Acad Sci U S A 110:16874-9 |
| Lim, Yiting; Hedayati, Mohammad; Merchant, Akil A et al. (2012) Chloroquine improves survival and hematopoietic recovery after lethal low-dose-rate radiation. Int J Radiat Oncol Biol Phys 84:800-6 |
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| Derheimer, Frederick A; Kastan, Michael B (2010) Multiple roles of ATM in monitoring and maintaining DNA integrity. FEBS Lett 584:3675-81 |
| Alexander, Angela; Cai, Sheng-Li; Kim, Jinhee et al. (2010) ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci U S A 107:4153-8 |
| Chandhasin, Chandtip; Ducu, Razvan I; Berkovich, Elijahu et al. (2008) Human T-cell leukemia virus type 1 tax attenuates the ATM-mediated cellular DNA damage response. J Virol 82:6952-61 |
| Rainey, Michael D; Charlton, Maura E; Stanton, Robert V et al. (2008) Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation. Cancer Res 68:7466-74 |
| Tang, Xi; Hui, Zhou-Guang; Cui, Xiao-Li et al. (2008) A novel ATM-dependent pathway regulates protein phosphatase 1 in response to DNA damage. Mol Cell Biol 28:2559-66 |
| Maclean, Kirsteen H; Dorsey, Frank C; Cleveland, John L et al. (2008) Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J Clin Invest 118:79-88 |
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