1. Ataxia Telangiectasia (AT) By Brandy Chapman

2. Characteristics of Ataxia- telangiectasia: Progressive neuronal degeneration Loss of cerebellar function Immunodeficiency Sterility Clinical radiation sensitivity Cancer predisposition

3. Important Definitions Ataxia: poor coordination of movement, including wide-based, uncoordinated, unsteady gait Associated with dysfunction of the cerebellum Telangiectasia: dilation of small blood vessels and capillaries usually of the sclera, face, and ears

4. Causes of Ataxia-telangiectasia Hereditary ataxia –A 7;14 chromosome translocation –Truncation of the AT gene Acquired ataxia related to –Alcoholism –Vitamin deficiencies –Multiple sclerosis –Vascular disease –Primary or metastatic tumors

5. Ataxia-telangiectasia is a hereditary, autosomal recessive disease

6. Diagnosis and Testing Genetic forms of the disease: –Family history –Physical examination –Neuro-imaging –Karyotyping Non-genetic forms: molecular genetic tests

7. About AT….. A childhood disorder, generally detected between the ages 1-4 Atrophy of the cerebellum, generally death by mid twenties Heterozygotes are asymptomatic Prenatal testing is available

8. Molecular Biology of AT AT is due to loss of function of the AT gene encoding the ATM protein The ATM protein is a master regulator in a DNA damage response cycle or checkpoint ATM –Location: Chromosome 11, q22 –A nuclear protein with a PI-3 K domain(phosphatidylinositol 3-kinase) on the carboxy terminus

9. ATM

10. Normal function of ATM A high molecular weight serine/threonine protein kinase with a PI-3 domain necessary for proper response to Double Stranded DNA Breakage Related to MEC1/ERS1 in S. cerevisiae, Rad3 in S. pombe and Mei-41 in Drosophilae Present in all cells with higher expression in the testis, spleen, and thymus Possibly activated by C1D, which responds to DNA breaks, via the leucine zipper motif Requires presence of Mn 2+ for function

11. ATM Function in Cell Cycle Checkpoints DNA DS break  ATM  p53 at serine 15 Ser15 controls the binding of p53 to mdm2 Mdm2: 1. inhibits transactivation by p53 2. targets p53 for proteolytic degradation when bound Phosphorylation of ser15 stabilizes p53 by limiting its ability to bind to mdm2 ATM may also activate a p53-specific phosphatase, dephosphorylating ser 376, promoting enhanced DNA binding activity

14. ATM Deficiency Contributes to Cancer Without ATM, p53 is not activated in response to DS DNA breaks and the cell fails to arrest in G1 or undergo apoptosis Loss of ATM leads to –Increased frequency of spontaneous chromosome rearrangement and telomeric fusions –Accelerated telomere shortening –Increased rates of intra- and extra-homologous recombination events –Increased numbers of chromosome gaps and breaks –Radiosensitivity and IR-induced chromosome instability

17. Cancers Commonly Associated with Ataxia-Telangiectasia Acute Lymphocytic Leukemias and lymphomas Epithelial tumors Thymic tumors Breast Cancer