Journal of Biological Chemistry
Volume 279, Issue 45, 5 November 2004, Pages 46359-46362
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MDC1 Regulates DNA-PK Autophosphorylation in Response to DNA Damage*

https://doi.org/10.1074/jbc.C400375200Get rights and content
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DNA damage initiates signaling events through kinase cascades that result in cell cycle checkpoint control and DNA repair. However, it is not yet clear how the signaling pathways relay to DNA damage repair. Using the repeat region of checkpoint protein MDC1 (mediator of DNA damage checkpoint protein 1), we identified DNA-PKcs/Ku as MDC1-associated proteins. Here, we show that MDC1 directly interacts with the Ku/DNA-PKcs complex. Down-regulation of MDC1 resulted in defective phospho-DNA-PKcs foci formation and DNA-PKcs autophosphorylation, suggesting that MDC1 regulates autophosphorylation of DNA-PKcs following DNA damage. Furthermore, DNA-PK-dependent DNA damage repair is defective in cells depleted of MDC1. Taken together, these results suggest that the MDC1 repeat region is involved in protein-protein interaction with DNA-PKcs/Ku, and MDC1 regulates DNA damage repair by influencing DNA-PK autophosphorylation. Therefore, MDC1 acts not only as a mediator of DNA damage checkpoint but also as a mediator of DNA damage repair.

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*

This work was supported by National Institutes of Health Grants NIH RO1 CA89239 and CA92312 (to J. C.) and CA50519 (to D. J. C.), Department of Energy Grant AG18949 (to D. J. C.), and by the Prospect Creek Foundation and the Breast Cancer Research Foundation. 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. S1–S5.

§

Recipient of Department of Defense Breast Cancer Fellowship Award DAMD17-03-1-0610.

Present address: Molecular Radiation Biology Division, Dept. of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390.