JBC DNA damage antibodies

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M601895200v1
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Papers In Press, published online ahead of print April 20, 2006
J. Biol. Chem, 10.1074/jbc.M601895200
Submitted on February 28, 2006
Revised on April 20, 2006
Accepted on April 20, 2006

Nuclear ATM mediates the cellular response to DNA double strand breaks in human neuron-like cells

Sharon Biton, Inbal Dar, Leonid Mittelman, Yaron Pereg, Ari Barzilai, and Yosef Shiloh

Department of Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv 69978

Corresponding Author: yossih{at}post.tau.ac.il

The protein kinase ATM activates the cellular response to double strand breaks (DSBs), a highly cytotoxic DNA lesion. ATM is activated by DSBs and in turn phosphorylates key players in numerous damage response pathways. ATM is missing or inactivated in the autosomal recessive disorder ataxia-telangiectasia (A-T), which is characterized by neuronal degeneration, immunodeficiency, genomic instability, radiation sensitivity and cancer predisposition. The predominant symptom of A-T is a progressive loss of movement coordination due to ongoing degeneration of the cerebellar cortex and peripheral neuropathy. A major deficiency in understanding A-T is the lack of information on ATM's role in neurons. It is unclear whether the ATM-mediated DSB response operates in these cells similarly to proliferating cells. Furthermore, ATM was reported to be cytoplasmic in neurons and suggested to function in these cells in capacities other than the DNA damage response. Recently we obtained genetic-molecular evidence that the neuronal degeneration in A-T does result from defective DNA damage response. We therefore undertook to investigate this response in a model system of human neuron-like cells (NLCs) obtained by neuronal differentiation in culture. ATM was largely nuclear in NLCs, and their ATM-mediated responses to DSBs were similar to those of proliferating cells. Knocking down ATM did not interfere with neuronal differentiation, but abolished ATM-mediated damage responses in NLCs. We concluded that nuclear ATM mediates the DSB response in NLCs similarly to in proliferating cells. Attempts to understand the neurodegeneration in A-T should be directed to investigating the DSB response in the nervous system.


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