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J. Biol. Chem., Vol. 281, Issue 9, 5532-5538, March 3, 2006

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Phosphorylation of Histones by Tissue Transglutaminase^*

Suresh Mishra, Ali Saleh, Paula S. Espino¹, James R. Davie², and Liam J. Murphy^¶3

From the Departments of Physiology, Biochemistry and Medical Genetics & ^¶Internal Medicine, University of Manitoba, Winnipeg R3E 0W3, Canada

Tissue transglutaminase 2 (TG2) has recently been shown to have intrinsic serine/threonine kinase activity. Since histones are known to be cross-linked by TG2, we investigated whether histones are also substrates for TG2 kinase activity. TG2 was able to phosphorylate H1, H2A, H2B, H3, and H4 histones in vitro. Using peptide substrates and phosphospecific antibodies we demonstrated that TG2 phosphorylated Ser¹⁰ in H3 and that this phosphorylation was reduced by acetylation, whereas phosphorylation of Ser¹⁰ by TG2 enhanced acetylation. Furthermore we demonstrated that exogenous TG2 phosphorylated H1 and H3 in nucleosome preparations. We examined the abundance of TG2 in DNA-associated proteins from MCF-7 cells treated with phorbol ester (TPA) and 17-estradiol (E2). TG2 abundance was significantly reduced in E2-treated cells and enhanced in TPA-treated cells. In summary we have demonstrated that TG2 is able to phosphorylate purified histone proteins, and H3 and H1 in chromatin preparations, and it is associated with chromatin in breast cancer cells. These studies suggest a novel role for TG2 in the regulation of chromatin structure and function.

Received for publication, June 23, 2005 , and in revised form, January 3, 2006.

^* This work was supported in part by a grant from the Canadian Institutes of Health Research (to L. J. M.) and by the National Cancer Institute of Canada with funds from the Canadian Cancer Society (to J. R. D.). 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 Recipient of a Guardian Angel studentship.

² Recipient of a Canada Research Chair.

³ Recipient of the Henry G. Friesen Endowed Research Professorship in Endocrine and Metabolic Diseases. To whom correspondence should be addressed: Rm. 843, John Buhler Research Centre, University of Manitoba, 715 McDermot Ave., Winnipeg MB R3E 3P4, Canada. Tel.: 204-789-3779; Fax: 204-789-3940; E-mail: ljmurph{at}cc.umanitoba.ca.

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