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J. Biol. Chem., Vol. 281, Issue 25, 17482-17491, June 23, 2006

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Nuclear Ataxia-Telangiectasia Mutated (ATM) Mediates the Cellular Response to DNA Double Strand Breaks in Human Neuron-like Cells^*

Sharon Biton¹, Inbal Dar, Leonid Mittelman^¶, Yaron Pereg, Ari Barzilai, and Yosef Shiloh²

From the The David and Inez Myers Laboratory for Genetic Research, Department of Molecular Genetics and Biochemistry, and ^¶Interdepartmental Core Facility, Sackler School of Medicine, and Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel

The protein kinase ATM (ataxia-telangiectasia mutated) 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 the role of ATM 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.

Received for publication, February 28, 2006 , and in revised form, April 20, 2006.

^* This work was supported by research grants from the A-T Children's Project, the A-T Medical Research Foundation, and National Institutes of Health Grant NS31763. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ This work was carried out in partial fulfillment of the requirements for the Ph.D. degree of S. B.

² To whom correspondence should be addressed. Tel.: 972-3-640-9760; Fax: 972-3-640-7471; E-mail: yossih{at}post.tau.ac.il.

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