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ATM , Ataxia Telangiectasia , & Cancer

ATM , Ataxia Telangiectasia , & Cancer. Ataxia Telangiectasia. Characterized by: Cerebellar deterioration Oculocutaneous telangiectasia Immunodeficiency Genomic Instability Acute sensitivity to ionizing radiation Predisposition to malignancy.

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ATM , Ataxia Telangiectasia , & Cancer

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  1. ATM,Ataxia Telangiectasia,& Cancer

  2. Ataxia Telangiectasia Characterized by: • Cerebellar deterioration • Oculocutaneous telangiectasia • Immunodeficiency • Genomic Instability • Acute sensitivity to ionizing radiation • Predisposition to malignancy

  3. The ATM gene was discovered by positional cloning • Chromosome 11q22 • 150kb • 66 exons Savitsky et. al. “A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase”

  4. ATM is a serine/threonine kinase • PI3K-related protein kinase family (a.k.a. PIKK) • Present in undamaged cell nuclei in inactive state • In response to DNA damage, becomes active and phosphorylates multiple substrates

  5. Cellular Response to DNA Damage

  6. ATM G1/S checkpoint P P P CHK2 P MDM2 p53 p21 CDK2 G1 ARREST

  7. G1/S and G2/M Checkpoints ATM P P CHK2 CHK1 P P CDC25A Degradation and Cell Cycle Arrest

  8. ATM mediated activation of BRCA1 following DNA Damage ATM P P P CtIP CHK2 P BRCA1 DNA REPAIR

  9. ATM P H2AX Congregates at site of DSB and recruits repair factors such as the MRN complex, BRCA 1, and RAD 51

  10. ATM and Telomere maintenance A-T cells display abnormally shortened telomeres, abnormal association of chromosome ends, and telomere clustering

  11. Animal Model of A-T Barlow et. al. “Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia”

  12. Heterozygous Carriersof a mutated ATM gene • The belief that heterozygous carriers are predisposed to malignancy is controversial • Point mutations can have dominant negative effect

  13. Current Treatments for A-T • No gene therapy or A-T specific treatment exists • Symptomatic (such as neurorehabilitation) • Routine screenings for malignancies • Gamma-globulin injections • Iron chelator therapy?

  14. Sources • Shiloh, Yosef. "ATM and Related Protein Kinases: Safeguarding Genome Integrity." Nature Reviews: Cancer 3 (2003): 155-168. • McKinnon, Peter. "ATM and Ataxia Telangiectasia." EMBO Reports 5 (2004): 772-776. • Barlow, Et. Al.. "Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia." Cell 86.1 (1996): 159-171. • Savitsky, Et. Al.. "A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase." Science 268 (1995): 1749-1753. • Thompson, Et. Al.. "Cancer Risks and Mortality in Heterozygous ATM Mutation Carriers." Journal of the National Cancer Institute 97 (2005): 813-822. • Lu, Shu, and Kate Shen. "Atm-haploinsufficiency Enhances Susceptibility to Carcinogen-induced Mammary Tumors." Carcinogenesis 27 (2006): 848-855. • Scott, Et. Al.. "Missense Mutations but Not Allelic Variants Alter the Function of ATM by Dominant Interference in Patients with Breast Cancer." PNAS 99.2 (2002): 925-930. • Uhrhammer N, Bay JO, Perlman S, Gatti RA . Ataxia-Telangiectasia and variants. Atlas Genet Cytogenet Oncol Haematol. April 2002 .URL : http://AtlasGeneticsOncology.org/Deep/ATMID20006.html • Shackelford, Et. Al.. "Iron Chelators Increase the Resistance of Ataxia Telangeictasia Cells to Oxidative Stress." DNA Repair 3.10 (2004): 1263-1272. • Online Mendelian Inheritance in Man: ATM Gene. Ada Hamosh. 19 July 2007. Johns Hopkins University, Baltimore, MD. 7 Mar. 2008 <http://www.ncbi.nlm.nih.gov.libproxy.lib.unc.edu/entrez/dispomim.cgi?id=607585>.

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