Transcript Ataxia- telangiectasia Mutated (ATM)

Ataxia- telangiectasia
Mutated (ATM)
Brooke Register
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
DNA Damage
DNA can be damaged from two sources:
1.
2.
Exogenous
Endogenous
At each checkpoint, if DNA is found to be damaged a
normal cell with either:
1.
2.
Repair the DNA or
Commit apoptosis
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.
DSB
Repair
Shiloh 2003.
The primary transducer in DSB
repair is…..
ATM
ATM- The Basics
Shiloh 2003.


Serine/ Threonine Kinase
Part of the PI3K- related protein kinase
family
PI3K Family Members
PI3K Domain
-Responds to various
stresses through the
phosphorylation
-located near the c-terminus
Shiloh 2003.
The Many Roles of ATM
1.
2.
3.
4.
Respond to DNA damage
Controls cell-cycle checkpoints
Linked to maintenance of
telomere length and integrity
Involved in breakage and
reunion of DNA
Shiloh 2003.
DSB Repair
Response
Web
ATM Signaling Pathway
MRN complex
McKinnon 2004.
Mutation

Mutation of the kinase domain of ATM gives
rise to ataxia telangiectasia (AT)

There are two main outcomes of ATM
mutations
ataxia telangiectasia

AT is a genomic instability syndrome


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Chromosomal instability
Radiosensitivity
Failure to activate cell cycle checkpoints
ataxia
telangiectasia

AT is human
autosomal recessive
1-2% of the general
population are carriers
McKinnon 2004.
ATM Knockout Mice

ATM knockout is not lethal

ATM knockout mice show premature aging
similar to human features of AT
ATM Knockout Mice
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
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: 497503.
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.
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