ataxia- telangiectasia mutated (atm) brooke register
TRANSCRIPT
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Ataxia- telangiectasia Mutated (ATM)
Brooke Register
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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
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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
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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.
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DSB Repair
Shiloh 2003.
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The primary transducer in DSB repair is…..
ATM
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ATM- The Basics
Serine/ Threonine Kinase Part of the PI3K- related protein kinase
family
Shiloh 2003.
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PI3K Family Members
PI3K Domain
-Responds to various stresses through the phosphorylation
-located near the c-terminus
Shiloh 2003.
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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
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DSB Repair Response WebShiloh 2003.
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ATM Signaling Pathway
McKinnon 2004.
MRN complex
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Mutation
Mutation of the kinase domain of ATM gives
rise to ataxia telangiectasia (AT)
There are two main outcomes of ATM mutations
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ataxia telangiectasia
AT is a genomic instability syndrome Chromosomal instability Radiosensitivity Failure to activate cell cycle checkpoints
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ataxia telangiectasia
AT is human autosomal recessive 1-2% of the general
population are carriers
McKinnon 2004.
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ATM Knockout Mice
ATM knockout is not lethal
ATM knockout mice show premature aging similar to human features of AT
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ATM Knockout Mice
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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
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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.
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