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J. Biol. Chem., Vol. 280, Issue 19, 18771-18781, May 13, 2005

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Mdm2 Binds to Nbs1 at Sites of DNA Damage and Regulates Double Strand Break Repair^*

Jodi R. Alt, Alyssa Bouska, Mario R. Fernandez, Ronald L. Cerny¶, Hua Xiao, and Christine M. Eischen||

From the Eppley Institute for Research in Cancer and the Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198 and the ^¶Department of Chemistry, University of Nebraska, Lincoln, Nebraska 68588

Mdm2 directly regulates the p53 tumor suppressor. However, Mdm2 also has p53-independent activities, and the pathways that mediate these functions are unresolved. Here we report the identification of a specific association of Mdm2 with Mre11, Nbs1, and Rad50, a DNA double strand break repair complex. Mdm2 bound to the Mre11-Nbs1-Rad50 complex in primary cells and in cells containing inactivated p53 or p14/p19^ARF, a regulator of Mdm2. Further analysis revealed that Mdm2 directly bound to Nbs1 but not to Mre11 or Rad50. Amino acids 198–314 of Mdm2 were required for Mdm2/Nbs1 association, and neither the N terminus forkhead-associated and breast cancer C-terminal domains nor the C terminus Mre11 binding domain of Nbs1 mediated the interaction of Nbs1 with Mdm2. Mdm2 co-localized with Nbs1 to sites of DNA damage following -irradiation. Notably, Mdm2 overexpression inhibited DNA double strand break repair, and this was independent of p53 and ARF, the alternative reading frame of the Ink4alocus. The delay in DNA repair imposed by Mdm2 required the Nbs1 binding domain of Mdm2, but the ubiquitin ligase domain in Mdm2 was dispensable. Therefore, Nbs1 is a novel p53-independent Mdm2 binding protein and links Mdm2 to the Mre11-Nbs1-Rad50-regulated DNA repair response.

Received for publication, November 29, 2004 , and in revised form, February 8, 2005.

^* The research was supported by NCI, National Institutes of Health (NIH), Grant CA09139 (to C. M. E.), NCI Training Grant CA09476 (to J. R. A. and M. R. F), American Cancer Society Research Scholar Grant RSG0216501GMC (to H. X.), Nebraska Cancer and Smoking Disease Research Program 04-11, the Eppley Institute for Research in Cancer, and the Wanda Rizzo Memorial Fund. The mass spectrometry facility is supported in part by NIH Grant P20 RR15635 from the COBRE program of the National Center for Research Resources, NCI, NIH, Cancer Center Support Grant P30 CA36727, and the Nebraska Research Initiative. 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.

^|| A Leukemia and Lymphoma Society Scholar. To whom correspondence should be addressed: Eppley Institute for Research in Cancer, 987696 Nebraska Medical Center, Omaha, NE 68198. Tel.: 402-559-3894; Fax: 402-559-3739; E-mail: ceischen{at}unmc.edu.

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