ATM,
Ataxia Telangiectasia, & Cancer
Ataxia Telangiectasia
Characterized by:• Cerebellar deterioration• Oculocutaneous telangiectasia • Immunodeficiency• Genomic Instability• Acute sensitivity to ionizing
radiation• Predisposition to malignancy
The ATM gene was discovered by positional cloning
• Chromosome 11q22• 150kb• 66 exons
Savitsky et. al. “A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase”
ATM is a serine/threonine kinase
• PI3K-related protein kinase family (a.k.a. PIKK)• Present in undamaged cell nuclei in inactive state• In response to DNA damage, becomes active and
phosphorylates multiple substrates
Cellular Response to DNA Damage
G1/S checkpoint
ATM
p53
P
CHK2
P
P
MDM2
P
p21 CDK2 G1ARREST
G1/S and G2/M Checkpoints
ATM
CHK1 CHK2
P P
CDC25AP P
Degradation and Cell Cycle Arrest
ATM mediated activation of BRCA1 following DNA Damage
ATM
BRCA1
CHK2
P
P
PCtIP
P
DNA REPAIR
ATM
H2AX
P
Congregates at site of DSB and recruits repair factors such asthe MRN complex, BRCA 1, and RAD 51
ATM and Telomere maintenance
A-T cells display abnormally shortened telomeres, abnormal association of chromosome ends, and telomere clustering
Animal Model of A-T
Barlow et. al. “Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia”
Heterozygous Carriersof a mutated ATM gene
• The belief that heterozygous carriers are predisposed to malignancy is controversial
• Point mutations can have dominant negative effect
Current Treatments for A-T
• No gene therapy or A-T specific treatment exists • Symptomatic (such as neurorehabilitation)• Routine screenings for malignancies• Gamma-globulin injections
• Iron chelator therapy?
Sources• Shiloh, Yosef. "ATM and Related Protein Kinases: Safeguarding Genome Integrity." Nature Reviews: Cancer 3
(2003): 155-168. • McKinnon, Peter. "ATM and Ataxia Telangiectasia." EMBO Reports 5 (2004): 772-776. • Barlow, Et. Al.. "Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia." Cell 86.1 (1996): 159-171.• Savitsky, Et. Al.. "A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase." Science 268
(1995): 1749-1753. • Thompson, Et. Al.. "Cancer Risks and Mortality in Heterozygous ATM Mutation Carriers." Journal of the National
Cancer Institute 97 (2005): 813-822. • Lu, Shu, and Kate Shen. "Atm-haploinsufficiency Enhances Susceptibility to Carcinogen-induced Mammary
Tumors." Carcinogenesis 27 (2006): 848-855. • Scott, Et. Al.. "Missense Mutations but Not Allelic Variants Alter the Function of ATM by Dominant Interference in
Patients with Breast Cancer." PNAS 99.2 (2002): 925-930. • Uhrhammer N, Bay JO, Perlman S, Gatti RA . Ataxia-Telangiectasia and variants. Atlas Genet Cytogenet Oncol
Haematol. April 2002 .URL : http://AtlasGeneticsOncology.org/Deep/ATMID20006.html
• Shackelford, Et. Al.. "Iron Chelators Increase the Resistance of Ataxia Telangeictasia Cells to Oxidative Stress." DNA Repair 3.10 (2004): 1263-1272.
• Online Mendelian Inheritance in Man: ATM Gene. Ada Hamosh. 19 July 2007. Johns Hopkins University, Baltimore, MD. 7 Mar. 2008 <http://www.ncbi.nlm.nih.gov.libproxy.lib.unc.edu/entrez/dispomim.cgi?id=607585>.