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J. Biol. Chem., Vol. 283, Issue 46, 31608-31616, November 14, 2008

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Disassembly of MDC1 Foci Is Controlled by Ubiquitin-Proteasome-dependent Degradation^*

Wei Shi, Zhefu Ma, Henning Willers^¶, Kamal Akhtar, Shaun P. Scott, Jiuqin Zhang, Simon Powell^||, and Junran Zhang¹

From the Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri 63108, the Breast Center, Department of Surgery, First Affiliated Hospital, Nanchang University, Nanchang 330006, China, the ^¶Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, and the ^||Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065

The orderly recruitment, retention, and disassembly of DNA damage response proteins at sites of damaged DNA is a conserved process throughout eukaryotic evolution. The recruitment and retention of DNA repair factors in foci is mediated by a complex network of protein-protein interactions; however, the mechanisms of focus disassembly remain to be defined. Mediator of DNA damage checkpoint protein 1 (MDC1) is an early and key component of the genome surveillance network activated by DNA double-strand breaks (DSBs). Here, we investigated the disassembly of MDC1 foci. First, we show that ubiquitylation directs the MDC1 protein for proteasome-dependent degradation. Ubiquitylated MDC1 associates with chromatin before and after exposure of cells to ionizing radiation (IR). In addition, increased MDC1 ubiquitylation in the chromatin fraction is observed in response to IR, which is correlated with a reduction in total MDC1 protein levels. We demonstrate that blocking MDC1 degradation by proteasome inhibitors leads to a persistence of MDC1 foci. Consistent with this observation, chromatin immunoprecipitation experiments reveal increased MDC1 protein at site-specific DSBs. Interestingly, we show that the persistence of MDC1 foci is associated with an abrogated recruitment of the downstream factor BRCA1 in a manner that is RNF8 independent. Collectively, the evidence presented here supports a novel mechanism for the disassembly of MDC1 foci via ubiquitin-proteasome dependent degradation, which appears to be a key step for the efficient assembly of BRCA1 foci.

Received for publication, February 11, 2008 , and in revised form, August 29, 2008.

^* This work was supported by a seed grant and startup fund from the Department of Radiation Oncology, Washington University School of Medicine, by the Dr. Joseph Roti Roti and Stephanie Pagano Fund for Mesothelioma Research, and by Grant IRG-58-010-51 from the American Cancer Society (to J. Z.). 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.

¹ To whom correspondence should be addressed: Dept. of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park Boulevard, St. Louis, MO 63108. Tel.: 314-747-5448; Fax: 314-747-9790; E-mail: jzhang{at}radonc.wustl.edu.

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