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 Ataxia Ocular telangiectasia Immunodeficiency Radiosensitivity Cancer Caused by null mutations in the ATM protein 1 in 40-100,000 Americans and Brits Ataxia-loss of coordination, usually wheelchair-bound by 10 or 20 Telangiectasia-Prominent blood vessels in the whites of the eyes Immunodeficiency-cannot form immunglobulins correctly

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 After breakage, the two molecules of the dimer phosphorylate each other to activate it

ATM has many Substrates NBS1: intra-S checkpoint, DNA repair BRCA1: activates checkpoint P53: G1S, enhanced activity CHK2: G1S 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, 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) Homozygous null ATM mutants die from thymic tumors within 4 months after birth Mice with a homozygous 3aa∆ producing nearly full-length but non-functional ATM live longer than null, but still develop tumors Heterozygous mice with truncation 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 either missense or null/truncations; 89% of A-T patients have truncated or null ATM proteins (Gilad et al., 1996) Missense mutations often produce less functional protein or kinase activity, NOT null, and therefore cause milder forms of A-T

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 (Gumy- Pause 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, 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? The effects in Arabidopsis thaliana of the de-activation of a gene homologous to the human ATM gene have been characterised and described. The human ATM gene is involved in the response to DNA damage, and its modification is responsible for the disease ataxia-telangiectasia, which is characterised among other things by chromosomal disorders, greater predisposition to cancers and high sensitivity to radiation. The de-activation of this gene in Arabidopsis thaliana induces a hypersensitivity to gamma radiation correlated with an inability to induce the transcription of genes involved in the detection and repair of DNA breaks, and also partial sterility due to a high occurrence of chromosome fragmentation during meiosis. These results show that this gene plays a central role in the response to DNA damage during stress and in the course of growth. They also provide important information on the mechanisms by which DNA damage is signalled in plants, about which little is known, unlike those in yeast or mammalian cells. These results were also the subject of editorial comment. Plant Cell (2003), 15 : 119-132Contact: Alain Tissier – DEVM 04.42.25.77.28 - tissier@dsvcad.cea.fr 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.

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