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

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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

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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