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J. Biol. Chem., Vol. 280, Issue 37, 32053-32056, September 16, 2005

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Structure of the BRCT Repeat Domain of MDC1 and Its Specificity for the Free COOH-terminal End of the -H2AX Histone Tail^*

From the Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

MDC1 (mediator of DNA damage checkpoint protein 1) regulates the recognition and repair of DNA double strand breaks in mammalian cells through its interactions with nuclear foci containing the COOH-terminally phosphorylated form of the histone variant, H2AX. Here we demonstrate that the tandem BRCT repeats of MDC1 directly bind to the phosphorylated tail of H2AX-Ser(P)-Gln-Glu-Tyr, in a manner that is critically dependent on the free carboxylate group of the COOH-terminal Tyr residue. We have determined the x-ray crystal structure of the MDC1 BRCT repeats at 1.45 Å resolution. By a comparison with the structure of the BRCA1 BRCT bound to a phosphopeptide, we suggest that two arginine residues in MDC1, Arg¹⁹³² and Arg¹⁹³³ may recognize the COOH terminus of the peptide as well as the penultimate Glu of H2AX, while Gln²⁰¹³ may provide additional specificity for the COOH-terminal Tyr.

Received for publication, June 23, 2005 , and in revised form, July 19, 2005.

^* This work was supported by grants from the National Cancer Institute of Canada and the Canadian Institutes of Health Research and by the Alberta Synchrotron Institute (for synchrotron access funding). 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 atomic coordinates and structure factors (code 2ADO) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http/www.rcsb.org/).

¹ Supported by an Alberta Heritage Foundation for Medical Research Studentship.

² Awarded a Canada Research Chair. To whom correspondence should be addressed: Dept. of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada. Tel.: 780-492-2136; Fax: 780-492-0886; E-mail: mark.glover{at}ualberta.ca.

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