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Ataxia telangiectasia and the Role of ATM Mary Christoph March 19, 2009 Graham, K. (2009, February 23). Brain tumour following neural (embryonic) stem cell transplant. Connecting for kids. <repairstemcell.wordpress.com/.../> Rare autosomal recessive disease Ataxia Ocular telangiectasia Immunodeficiency Radiosensitivity Cancer Caused by null mutations in the ATM protein 350kD serine-threonine kinase, C11 Lipid Phosphatidylinositol 3kinase (PI(3)K) domain has kinase activity Double-strand break in DNA (DSB) causes ATM autophosphorylation Phosphorylates at least a dozen more substrates NBS1: intra-S checkpoint, DNA repair BRCA1: activates checkpoint P53: G1S, enhanced activity CHK2: G1S checkpoint kinase, activated MDM2: ubiquitin ligase acting on p53, no longer bind and degrade p53 ATM activation leads to either DNA repair or apoptosis ATM activated at DSB sites, which starts a cascade to either repair the DNA or cause apoptosis when the damage is extensive. When ATM is mutated, however, it cannot adequately regulate its substrates, which include many proteins essential for the cell cycle, especially cell-cycle checkpoints (Shiloh, 2003). Likely redundancy because homozygous null mutants survive (cite) Knockout Mouse Model Homozygous null ATM mutants die within 4 months Mice homozygous for nearly full-length, nonfunctional ATM live longer than null, but still develop tumors Heterozygous mice with null mutations have no greater risk than wt; 3aa∆ heterozygotes develop tumors (Spring et al., 2002) Ozturk N. et.al. PNAS 2009;106:2841-2846 Human ATM mutations produce different effects depending on type Mutations Can be… Null/Truncated Missense 89% of all A-T cases, severe 11% of cases, milder ATM mutations cause cancer predisposition Heterozygous humans (0.5-1% of the population) are more likely to develop cancer (Thorstenson et al., 2003), perhaps due to LOH (Gumy-Pause et al., 2004). Mutations affecting kinase activity are implicated in tumor formation (Spring et al., 2002) Tumor types are usually leukemia or lymphoma (GumyPause et al., 2004)lack of immune system maturation, DNA breakage and processing, without ATM (Perkins et al., 2002) Web Pathology, Genitourinary Tract. (2008). Hepatosplenic T-cell Lymphoma. Retrieved March 18, 2009 from Web site: webpathology.com/image.asp?case=378&n=15 Importance of the highly-conserved ATM DNA repair/apoptosis Conserved in mice, What are the redundant proteins? humans, Arabidopsis Mutations either truncated or missense, especially interrupted kinase activity in cancers, inadequate phosphorylation of substrates Which mutations cause cancer? Why does heterozygosity increase cancer risk? References Gilad, S. et al. (1996). Predominance of null mutations in ataxiatelangiectasia. Human Molecular Genetics 5:433-439. Gumy-Pause, F. et al. (2004). ATM gene and lymphoid malignancies. Leukemia 18:238-242. Thorstenson, Y.R. et al. (2003). Contributions of ATM Mutations to Familial Breast and Ovarian Cancer. Cancer Research 63:33253333. McKinnon, P.J. (2004). ATM and ataxia telangiectasia. EMBO reports 5:772-776. Shiloh, Y. (2003). ATM and related protein kinases: safeguarding genome integrity. Nature Reviews 3:155-168. Spring, K. (2002). Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer. Nature Genetics 32:185-190.