1. ATM John Berry

2. What is ATM? Named “ATM” for “Ataxia-telangiectasia Mutated” gene. The mutation is recessive. Named “ATM” for “Ataxia-telangiectasia Mutated” gene. The mutation is recessive. Ataxia-telangiectasia (or AT) is a neurodegenerative disease that is normally detected in infancy to early childhood. Ataxia-telangiectasia (or AT) is a neurodegenerative disease that is normally detected in infancy to early childhood. AT patients have shown a predisposition to Lymphoma, so ATM was suspected as a tumor suppressing gene. AT patients have shown a predisposition to Lymphoma, so ATM was suspected as a tumor suppressing gene.http://my.webmd.com/hw/health_guide_atoz/nord406.asp

3. AT Symptoms Symptoms: ataxia, telangiectasia, and impairing of the immune system Symptoms: ataxia, telangiectasia, and impairing of the immune systemhttp://my.webmd.com/hw/health_guide_atoz/nord406.asp

4. AT Symptoms Symptoms: ataxia, telangiectasia, and impairing of the immune system Symptoms: ataxia, telangiectasia, and impairing of the immune systemhttp://www.uv.es/derma/CLindex/CLlinfomas/CLmast9.jpghttp://my.webmd.com/hw/health_guide_atoz/nord406.asp

5. AT Effects Patients are subject to sinopulmonary infections Patients are subject to sinopulmonary infections Increased occurrence of malignant tumors. Increased occurrence of malignant tumors. Patients have a short life-expectancy. Patients have a short life-expectancy.http://my.webmd.com/hw/health_guide_atoz/nord406.asp

6. ATM P(3)IK Serine-Threonine Kinase P(3)IK Serine-Threonine Kinase Located in the Nucleus Located in the Nucleus Normally inactivated Normally inactivated Rapid activation in response to Double Strand Break (DSB) Rapid activation in response to Double Strand Break (DSB) Substrate list is not presently complete. Substrate list is not presently complete.

7. ATM Function http://jncicancerspectrum.oupjournals.org.libproxy.lib.unc.edu/cgi/reprint/jnci;92/10/795.pdf

8. ATM Substrates http://jncicancerspectrum.oupjournals.org.libproxy.lib.unc.edu/cgi/reprint/jnci;92/10/795.pdf

9. ATM Checkpoint Functions ATM Checkpoint Functions Shiloh, Yosef. “ATM AND RELATED PROTEIN KINASES: SAFEGUARDING GENOMEINTEGRITY.” Nature Reviews Cancer. Volume 3 March 2003 pg 155-168

10. Repair McKinnon, Peter J. “ATM and Ataxia telangiectasia.”Embo Reports. Vol 3 (8) 2004. pg 772-776

11. ATM knockout in Mice ATM -/-: Lymphoma in 2-4 months ATM -/-: Lymphoma in 2-4 months Heterozygous mice are predisposed. Heterozygous mice are predisposed. Loss of Heterozygosity is required in most cases Loss of Heterozygosity is required in most cases Barlow, C, et al. “Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell. 1996 Jul 12;86(1):159-71.

12. Evidence for the Pathway http://breast-cancer-research.com/content/pdf/bcr968.pdf

13. ATM +/-, p53 +/- Mice Irradiated double heterozygous mice show the highest incidence of carcinogenesis http://breast-cancer- research.com/content/pdf/bcr9 68.pdf

14. ATM mutations in Human Cancer A-T Patients are not the main health concern, but rather carriers of A-T. A-T Patients are not the main health concern, but rather carriers of A-T. Most heterozygous individuals do not show a pre-disposition to cancer Most heterozygous individuals do not show a pre-disposition to cancer Discovery of the dominant negative Discovery of the dominant negative Shiloh, Yosef. “ATM AND RELATED PROTEIN KINASES: SAFEGUARDING GENOMEINTEGRITY.” Nature Reviews Cancer. Volume 3 March 2003 pg 155-168

15. ATM Function http://jncicancerspectrum.oupjournals.org.libproxy.lib.unc.edu/cgi/reprint/jnci;92/10/795.pdf

16. Future Directions Despite a limited risk group, ATM is still important for research. Despite a limited risk group, ATM is still important for research. Damage repair is a key component of homeostasis. Damage repair is a key component of homeostasis.

17. Any Questions?