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J. Biol. Chem., Vol. 282, Issue 48, 35416-35423, November 30, 2007

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MCPH1 Functions in an H2AX-dependent but MDC1-independent Pathway in Response to DNA Damage^*

Jamie L. Wood¹, Namit Singh^¶, Georges Mer^¶, and Junjie Chen²

From the Departments of Molecular Pharmacology and Experimental Therapeutics and ^¶Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905 and Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520

Microcephalin (MCPH1) is one of the causative genes for the autosomal recessive disorder, primary microcephaly, characterized by dramatic reduction in brain size and mental retardation. MCPH1 also functions in the DNA damage response, participating in cell cycle checkpoint control. However, how MCPH1 is regulated in the DNA damage response still remains unknown. Here we report that the ability of MCPH1 to localize to the sites of DNA double-strand breaks depends on its C-terminal tandem BRCT domains. Although MCPH1 foci formation depends on H2AX phosphorylation after DNA damage, it can occur independently of MDC1. We also show that MCPH1 binds to a phospho-H2AX peptide in vitro with an affinity similar to that of MDC1, and overexpression of wild type, but not C-BRCT mutants of MCPH1, can interfere with the foci formation of MDC1 and 53BP1. Collectively, our data suggest MCPH1 is recruited to double-strand breaks via its interaction with H2AX, which is mediated by MCPH1 C-terminal BRCT domains. These observations support that MCPH1 acts early in DNA damage responsive pathways.

Received for publication, June 26, 2007 , and in revised form, September 14, 2007.

^* This work was supported in part by National Institute of Health Grants CA092312 and CA100109 (to J. C.) and CA109449 (to G. M.). 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 Supported by National Research Service Award, National Institutes of Health Grant F31 GM770802.

² Recipient of a Department of Defense Era of Hope Scholar Award. To whom correspondence should be addressed. Tel.: 203-785-3758; Fax: 203-785-7482; E-mail: junjie.chen{at}yale.edu.

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