ataxia- telangiectasia mutated (atm) brooke register
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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. 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
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
Serine/ Threonine Kinase Part of the PI3K- related protein kinase
family
Shiloh 2003.
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. 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
DSB Repair Response WebShiloh 2003.
ATM Signaling Pathway
McKinnon 2004.
MRN complex
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 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: 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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