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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.
 Rare autosomal
recessive disease
 Ataxia
 Ocular
 Immunodeficiency
 Radiosensitivity
 Cancer
 Caused by null
mutations in the
ATM protein
 350kD serine-threonine
kinase, C11
 Lipid
Phosphatidylinositol 3kinase (PI(3)K) domain
has kinase activity
 Double-strand break in
DNA (DSB) causes ATM
 Phosphorylates at least a
dozen more substrates
 NBS1: intra-S
checkpoint, DNA
 BRCA1: activates
 P53: G1S, enhanced
 CHK2: G1S
checkpoint kinase,
 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
 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
 Mice homozygous for
nearly full-length, nonfunctional ATM live longer
than null, but still develop
 Heterozygous mice with
null mutations have no
greater risk than wt; 3aa∆
heterozygotes develop
tumors (Spring et al.,
Ozturk N. PNAS 2009;106:2841-2846
Human ATM mutations produce
different effects depending on type
Mutations Can be…
89% of all A-T cases,
11% of cases, milder
ATM mutations cause cancer
 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 (GumyPause 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
Importance of the highly-conserved ATM
 DNA repair/apoptosis
 Conserved in mice,
 What are the redundant proteins?
humans, Arabidopsis
 Mutations either truncated
or missense, especially
interrupted kinase activity
in cancers, inadequate
phosphorylation of
 Which mutations cause
 Why does heterozygosity
increase cancer risk?
 Gilad, S. et al. (1996). Predominance of
null mutations in ataxiatelangiectasia. 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 63:33253333.
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.