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ATM and Ataxia-Telangiectasia

ATM and Ataxia-Telangiectasia. Caroline Hunter Biology 169 March 23, 2006. Ataxia-telangiectasia: The disease. Genetic disorder characterized by: Cerebellar degeneration Hypersensitivity to ionizing radiation Immunodeficiency High cancer risk Disease occurs at 1/40,000 frequency

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ATM and Ataxia-Telangiectasia

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  1. ATM and Ataxia-Telangiectasia Caroline Hunter Biology 169 March 23, 2006

  2. Ataxia-telangiectasia: The disease • Genetic disorder characterized by: • Cerebellar degeneration • Hypersensitivity to ionizing radiation • Immunodeficiency • High cancer risk • Disease occurs at 1/40,000 frequency • Inherited in autosomal-recessive fashion

  3. A-T continued • Signs of the disease: • Problems with balance (ataxia) due to the death of Purkinje cells, which eventually leads to progressive neuronal degeneration • Prominent blood vessels in whites of eyes and on the face (telangiectasia) • No known cure and disease is fatal in 20s or 30s from recurrent respiratory infections (1/2 of cases) or cancer (1/3-1/2 of cases)

  4. What is the Ataxia-Telangiectasia Mutated (ATM) Gene? • Located on Chromosome 11 • Encodes a kinase of the phosphatidynlinsitol 3-kinase-related kinase (PIKK) family • Expressed in all tissues • Localized mainly in the nucleus throughout all stages of the cell cycle • Also found in the cytoplasm

  5. What is ATM’s normal biochemical and cell biological role?

  6. Dealing with DNA Damage • Corrects DNA damage that occurs because of: • Double Stranded Breaks (DSBs) • Homologous Recombination • In DSBs, acts as a first response • phosphorylates the core histone H2AX protein • H2AX marks the site of damage and recruits damage response and repair complexes

  7. Repairing DSBs

  8. A more detailed pathway

  9. What happened in knockout mice? • ATM -/- mice • Growth retardation • Radiosensitivity • Thymic lymphoma • Poor development of Purkinje and T cells • Selective neuron loss • Activated astrocytes • Sterility • Premature aging

  10. Mice, continued • ATM +/- mice: • Similar to wild type, but following radiation, experienced • Decreased survival • Premature graying • Higher levels of abnormal mammary epithelial cells • Radiation-induced cataracts

  11. In vitro models • ATM-deficient fibroblasts grew poorly and displayed high level of DSBs • ATM-deficient thymocytes underwent spontaneous apoptosis significantly more than controls

  12. How does ATM contribute to cancer? • Mutated ATM prevents correction of DSBs • The proliferation of messed up DNA is bad • Cells that are supposed to die, don’t • Mutated ATM prevents correct homologous recombination • Cancer develops in A-T patients 100 times higher than normal, especially breast cancer and leukemia

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