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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/.../ >. Ataxia telangiectasia. Rare autosomal recessive disease
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Ataxia telangiectasia and the Role of ATM Mary ChristophMarch 19, 2009 Graham, K. (2009, February 23). Brain tumour following neural (embryonic) stem cell transplant. Connecting for kids. <repairstemcell.wordpress.com/.../>
Ataxia telangiectasia Rare autosomal recessive disease Ataxia Ocular telangiectasia Immunodeficiency Radiosensitivity Cancer Caused by null mutations in the ATM protein
Characterizing ATM 350kD serine-threonine kinase, C11 Lipid Phosphatidylinositol 3-kinase (PI(3)K) domain has kinase activity Double-strand break in DNA (DSB) causes ATM autophosphorylation Phosphorylates at least a dozen more substrates
ATM has many 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 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) ATM activation leads to either DNA repair or apoptosis
Knockout Mouse Model • Homozygous null ATM mutants die within 4 months • Mice homozygous for nearly full-length, non-functional 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
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 (Gumy-Pause et al., 2004)lack of immune system maturation, DNA breakage and processing, without ATM (Perkins et al., 2002) ATM mutations cause cancer predisposition 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, 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? • What are the redundant proteins?
References • Gilad, S. et al. (1996). Predominance of null mutations in ataxia-telangiectasia. 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 63:3325-3333. • 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.
