1. ATM, Ataxia Telangiectasia, & Cancer

2. Ataxia Telangiectasia
Characterized by:
Cerebellar deterioration
Oculocutaneous telangiectasia
Immunodeficiency
Genomic Instability
Acute sensitivity to ionizing radiation
Predisposition to malignancy
Autosomal recessive
ATM -/- people are compound heterozygotes (the 2 ATM genes inherited do not have the same mutation) Several types of mutations have been found in the ATM gene of affected individuals with A-T.
Diagnosed in early childhood.
Cerebellar deterioration – leads to severe progressive neuromotor dysfunction
Telangiectasia= chronic dilation of blood vessels in the conjunctiva of the eye
Malignanices (10-15%): lymphoreticular (lymphoid leukemias and lymphomas most common), some epithelial
Death occurs by the age of 30

3. The ATM gene was discovered by positional cloning
Chromosome 11q22
150kb
66 exons
Cloned in 1995 by Savitsky et. al.
Located on chromosome 11q22
Gene is 150kb long and consists of 66 exons.
Savitsky et. al. “A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase”

4. ATM is a serine/threonine kinase
Protein is 3,056 aa’s long (350kDa)
Resides in the nucleus of cells.
Responds rapidly to DNA double stranded breaks.
In undamaged cells, it is inactive in dimers or multimers, in which the FAT domain blocks the kinase domain. When DNA damage is sensed, the ATM subunits auto-phosphorylate each other on the FAT domain, causing release from the multimer and conversion into active state. ATM then goes on to phosphorylate multiple substrates that participate in cell cycle check points and DNA damage repair.
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

5. Cellular Response to DNA Damage

6. G1/S checkpoint ATM CHK2 p53 G1 CDK2 ARREST MDM2 p21 P P P P
Upon sensing DNA damage and becoming activated, ATM phosphorylates p53 at Ser15
Goal: to activate and stabilize p53 to drive G1 arrest following DNA damage
CHK2 phos. of p53 interferes with p53-MDM2 interactions
ATM phos. Of MDM2 interferes with MDM2 exporting p53 out of the nucleus
p53 activates transcription of the p21 gene.
p21
CDK2 G1
ARREST

7. G1/S and G2/M Checkpoints
ATM P P
CHK2
CHK1 P P
CDC25A
CDC25A is a phosphatase that is responsible for activating CDK2 (G1S) and CDK1 (G2M). Therefore, its degradation prevents progression into the S or M phase.
Degradation and Cell Cycle Arrest

8. ATM mediated activation of BRCA1 following DNA DamageP P P
CtIP
CHK2 P
BRCA1
ATM phosphorylates BRCA1 at several sites.
Phosphorylation at one point activates BRCA1 as a regulator of the intra-S-phase checkpoint, at another activates it at the G2/M checkpoint.
DNA REPAIR

9. ATM P
H2AX
H2AX is a histone protein variant.
Congregates at site of DSB and recruits repair factors such as
the MRN complex, BRCA 1, and RAD 51

10. ATM and Telomere maintenance
A-T cells display
abnormally shortened telomeres, abnormal association of
chromosome ends,
and telomere clustering
ATM is functionally linked to the maintenance of telomere length and integrity.
This leads to chromosome instability, as telomeres of sister chromatids can fuse together and chromosome breakage can occur during mitosis.

11. Animal Model of A-T The mouse ATM protein is 84% similar to the human.
Created mouse knockout (ATM -/-) by gene targeting, created truncated form of the protein
They took a sequence that was commonly mutated in human A-T and used this sequence to insert a neo gene, creating a frameshift mutation that caused a truncated protein.
Mice display growth retardation, neurologic dysfunction, immunological abnormalities, lymphoreticular malignancies, chromosomal instability, infertility, sensitivity to IR.
develop malignant thymic lymphomas between 2-4 months of age.
Differences: mice do not display telangiectasia (possibly due to sun exposure in affected humans, or mice die from malignancy before this occurs)
no cerebellar degeneration seen in mice (probably because they die from malignancy before it can progress)
Barlow et. al. “Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia”

12. Heterozygous Carriers of a mutated ATM gene
The belief that heterozygous carriers are
predisposed to malignancy is controversial
Point mutations can have dominant negative effect
Thought that heterozygotes are predisposed to breast cancer.
Results of studies are conflicting
A study done in 2005 examined the medical histories of 1,160 blood relatives of A-T patients in the UK and estimated that the risk of developing breast cancer was greater than that of the general population.

13. 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?
Diagnostics using Xrays should be avoided. Treatment of malignancies is also difficult due to extreme sensitivity to radiation and other mutagenic agents.
IVIG treatment to improve immune system function.
Recent studies have shown that treatment of A-T cells in vitro with iron chelators such as apoferritin increases the cells’ abilities to form colonies and increases their resistance to oxidative stress. To my knowledge, this treatment has not yet been tried in A-T patients, but could be a promising treatment in the future.

14. Sources
Shiloh, Yosef. "ATM and Related Protein Kinases: Safeguarding Genome Integrity." Nature Reviews: Cancer 3 (2003):
McKinnon, Peter. "ATM and Ataxia Telangiectasia." EMBO Reports 5 (2004):
Barlow, Et. Al.. "Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia." Cell 86.1 (1996):
Savitsky, Et. Al.. "A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase." Science 268 (1995):
Thompson, Et. Al.. "Cancer Risks and Mortality in Heterozygous ATM Mutation Carriers." Journal of the National Cancer Institute 97 (2005):
Lu, Shu, and Kate Shen. "Atm-haploinsufficiency Enhances Susceptibility to Carcinogen-induced Mammary Tumors." Carcinogenesis 27 (2006):
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):
Uhrhammer N, Bay JO, Perlman S, Gatti RA . Ataxia-Telangiectasia and variants. Atlas Genet Cytogenet Oncol Haematol. April URL :
Shackelford, Et. Al.. "Iron Chelators Increase the Resistance of Ataxia Telangeictasia Cells to Oxidative Stress." DNA Repair 3.10 (2004):
Online Mendelian Inheritance in Man: ATM Gene. Ada Hamosh. 19 July Johns Hopkins University, Baltimore, MD. 7 Mar <