1. Ataxia- telangiectasia Mutated (ATM) Brooke Register

2. Cell Cycle Review The cell cycle has two major checkpoints. -Between the G1-S transition -Between the G2-M transition http://www.daviddarling.info/images/cell_cycle.jpg

3. DNA Damage DNA can be damaged from two sources: 1. Exogenous 2. Endogenous At each checkpoint, if DNA is found to be damaged a normal cell with either: 1. Repair the DNA or 2. Commit apoptosis

4. Double Stranded Break Naturally Occur with low level activity in: -meiotic recombination -assembly of T-cell receptors -immunoglobulin genes DSBs can be lethal in cells exposed to ionizing radiation or radiomimetic chemicals.

5. DSB Repair Shiloh 2003.

6. The primary transducer in DSB repair is….. ATM

7. ATM- The Basics Serine/ Threonine Kinase Part of the PI3K- related protein kinase family Shiloh 2003.

8. PI3K Family Members PI3K Domain -Responds to various stresses through the phosphorylation -located near the c-terminus Shiloh 2003.

9. The Many Roles of ATM 1. Respond to DNA damage 2. Controls cell-cycle checkpoints 3. Linked to maintenance of telomere length and integrity 4. Involved in breakage and reunion of DNA

10. DSB Repair Response Web Shiloh 2003.

11. ATM Signaling Pathway McKinnon 2004. MRN complex

12. Mutation Mutation of the kinase domain of ATM gives rise to ataxia telangiectasia (AT) There are two main outcomes of ATM mutations

13. ataxia telangiectasia AT is a genomic instability syndrome Chromosomal instability Radiosensitivity Failure to activate cell cycle checkpoints

14. ataxia telangiectasia AT is human autosomal recessive 1-2% of the general population are carriers McKinnon 2004.

15. ATM Knockout Mice ATM knockout is not lethal ATM knockout mice show premature aging similar to human features of AT

16. ATM Knockout Mice

17. ATM and Cancer Genetic instability is a hallmark of both AT and caner Cancer occurs in 10-38% of AT individuals Increased risk of cancer in the family members of AT patients Birrell 2004

18. References Aburatani H, Hishiya A, Ikeda K, Ito M, Motoyama N, Watanabe K. Ataxia telangiectasia mutated (Atm) knockout mice as a model of osteopenia due to impaired bone formation. Bone 2005; 37: 497- 503. Birrell G, Chen P, Gueven N, Kozlov S, Lavin M, Scott S. ATM signaling and genomic stability in response to DNA damage. Fundamental and Molecular Mechanisms of Mutagenesis 2005; 569: 123-132. McKinnon, Peter. ATM and ataxiz telangiectasia. EMBO reports 2004; 5: 772-776. Shiloh, Yosef. ATM and Related Protein Kinases: Safeguarding genome integrity. Nature Reviews 2003; 3: 155-169. http://www.daviddarling.info/images/cell_cycle.jpg