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J. Biol. Chem., Vol. 282, Issue 17, 12851-12859, April 27, 2007

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Poly(ADP-ribose) Polymerase 1 Is Inhibited by a Histone H2A Variant, MacroH2A, and Contributes to Silencing of the Inactive X Chromosome^*

Dmitri A. Nusinow¹, Inmaculada Hernández-Muñoz², Thomas G. Fazzio³, Girish M. Shah^¶, W. Lee Kraus^||, and Barbara Panning⁴

From the Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, the Unitat de Biologia Cellular i Molecular, Institut Municipal d'Investigació Mèdica, Dr. Aiguader, 80, 08003 Barcelona, Spain, the ^¶Laboratory for Skin Cancer Research, CHUL Research Center, Laval University, Ste. Foy, Quebec G1V 4G2, Canada, and the ^||Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853

Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that is involved in modulating chromatin structure, regulation of gene expression, and sensing DNA damage. Here, we report that PARP-1 enzymatic activity is inhibited by macroH2A, a vertebrate histone H2A variant that is enriched on facultative heterochromatin. MacroH2A family members have a large C-terminal non-histone domain (NHD) and H2A-like histone domain. MacroH2A1.2 and PARP-1 interact in vivo and in vitro via the NHD. The NHD of each macroH2A family member was sufficient to inhibit PARP-1 enzymatic activity in vitro. The NHD of macroH2A1.2 was a mixed inhibitor of PARP-1 catalytic activity, with affects on both catalytic activity and the substrate binding affinity of PARP-1. Depletion of PARP-1 by RNA interference caused reactivation of a reporter gene on the inactive X chromosome, demonstrating that PARP-1 participates in the maintenance of silencing. These results suggest that one function of macroH2A in gene silencing is to inhibit PARP-1 enzymatic activity, and this may affect PARP-1 association with chromatin.

Received for publication, November 10, 2006 , and in revised form, January 30, 2007.

^* This work was supported by National Institutes of Health Grant RO1GM63671, the Hellman Family Foundation, and the Pew Biomedical Scholars Program (to B. P.) and by National Institutes of Health Grant RO1DK069710 (to W. L. K.). 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. 1 and 2 and Ref. 1.

¹ Recipient of the University of California Dissertation Year Fellowship.

² Supported by Instituto de Salud Carlos III Grants CP04/00292 and PI05/1912.

³ A Jane Coffin Childs Fellow.

⁴ To whom correspondence should be addressed: Genentech Hall S372B, 600 16th St., Dept. of Biochemistry & Biophysics, University of California, San Francisco, CA 94158. Tel.: 415-514-0745; Fax: 415-514-4080; E-mail: bpanning{at}biochem.ucsf.edu.

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