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First published on May 16, 2007; DOI: 10.1124/mol.107.036681

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Received for publication April 4, 2007.
Revised May 16, 2007.
Accepted for publication May 16, 2007.

Characterization of an NBS1 C-terminal peptide that can inhibit ATM-mediated DNA damage responses and enhance radiosensitivity

Mickael J. Cariveau 1, Xi Tang 2, Xiao-Li Cui 3, Bo Xu 3*

1 Southern research Institute 2 LSU Health Sciences Center 3 Southern Research Institute

* Address correspondence to: E-mail: xu{at}sri.org

Abstract

ATM and NBS1, mutation of which lead to the human autosomal recessive diseases, Ataxia Telangiectasia (A-T) and Nijmegen Breakage Syndrome (NBS), respectively, are essential elements in the cellular response to ionizing radiation (IR)-induced DNA damage. ATM is a member of the PI-3K kinase family and is activated by IR in an NBS1-dependent manner. The extreme C-terminus of NBS1 contains an evolutionarily conserved sequence motif that is critical for binding to and activation of ATM after IR. ATM phosphorylates a series of targets to initiate cell cycle arrest and promote cell survival in response to DNA damage. Therefore, targeting the NBS1-ATM interaction may lead to a novel approach for specific ATM inhibition and radiosensitization. We developed small peptides containing the conserved C-terminal sequence of NBS1 to investigate whether these peptides can interfere with the DNA damage pathway. We found that wild-type NBS1 inhibitory peptides (wtNIP) can abrogate NBS1-ATM association in the presence or absence of IR. We also found that cells exposed to wtNIP displayed a significant reduction in radiation-induced {gamma}-H2AX and NBS1 focus formation compared to cells treated with control peptides, demonstrating that wtNIP possesses a strong inhibitory effect on ATM. The inhibitory effect of wtNIP also leads to a significant decrease in clonogenic survival in response to IR. Furthermore, wtNIP does not radiosensitize cells with defective ATM, suggesting a specific inhibition of ATM. Collectively, these data provide a proof of principle for the use of NBS1 C-terminal small peptides as specific ATM inhibitors and radiosensitizers.


Key words: DNA damage and repair, Tumor suppressors


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