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Characterization of an NBS1 C-Terminal Peptide That Can Inhibit Ataxia Telangiectasia Mutated (ATM)-Mediated DNA Damage Responses and Enhance Radiosensitivity

Department of Biochemistry and Molecular Biology, Southern Research Institute (M.J.C., X.-L.C., B.X.) and Comprehensive Cancer Center (M.J.C., X.-L.C., B.X.), University of Alabama at Birmingham, Birmingham, Alabama; and Department of Genetics, Louisiana State University Sciences Center, New Orleans, Louisiana (X.T.)

ATM and NBS1, mutation of which lead to the human autosomal recessive diseases ataxia telangiectasia and Nijmegen breakage syndrome (NBS), respectively, are essential elements in the cellular response to DNA damage induced by ionizing radiation (IR). ATM is a member of the phosphatidylinositol 3-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 -H2AX and NBS1 focus formation compared with 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. Together, these data provide a proof of principle for the use of NBS1 C-terminal small peptides as specific ATM inhibitors and radiosensitizers.

Address correspondence to: Bo Xu, MD, PhD, Southern Research Institute, Department of Biochemistry and Molecular Biology, 2000 9th Avenue South, Birmingham, AL 35205. E-mail: xu{at}sri.org32