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J. Biol. Chem., Vol. 283, Issue 28, 19478-19488, July 11, 2008

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Catalytic Function of the PR-Set7 Histone H4 Lysine 20 Monomethyltransferase Is Essential for Mitotic Entry and Genomic Stability^*

Sabrina I. Houston¹, Kirk J. McManus, Melissa M. Adams^¶, Jennifer K. Sims, Phillip B. Carpenter^¶2, Michael J. Hendzel, and Judd C. Rice, Pew Scholar in the Biomedical Sciences³

From the Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, California 90033, the Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta T6G 1Z2, Canada, and the ^¶Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas 77030

Histone-modifying enzymes play a critical role in modulating chromatin dynamics. In this report we demonstrate that one of these enzymes, PR-Set7, and its corresponding histone modification, the monomethylation of histone H4 lysine 20 (H4K20), display a distinct cell cycle profile in mammalian cells: low at G₁, increased during late S phase and G₂, and maximal from prometaphase to anaphase. The lack of PR-Set7 and monomethylated H4K20 resulted in a number of aberrant phenotypes in several different mammalian cell types. These include the inability of cells to progress past G₂, global chromosome condensation failure, aberrant centrosome amplification, and substantial DNA damage. By employing a catalytically dead dominant negative PR-Set7 mutant, we discovered that its mono-methyltransferase activity was required to prevent these phenotypes. Importantly, we demonstrate that all of the aberrant phenotypes associated with the loss of PR-Set7 enzymatic function occur independently of p53. Collectively, our findings demonstrate that PR-Set7 enzymatic activity is essential for mammalian cell cycle progression and for the maintenance of genomic stability, most likely by monomethylating histone H4K20. Our results predict that alterations of this pathway could result in gross chromosomal aberrations and aneuploidy.

Received for publication, December 31, 2007 , and in revised form, March 31, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant GM075094 (to J. C. R.). This work was also supported by generous funding from the Donald E. and Delia B. Baxter Foundation and the Robert E. and May R. Wright Foundation. 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. S1–S5.

¹ Supported by a grant from the California Breast Cancer Research Program.

² Supported by the National Institutes of Health Grant R56 GM065812 and by a generous grant from the Robert Welch Foundation Grant AU-1569.

³ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, 1450 Biggy St., NRT 6506, Los Angeles, CA 90033. Tel.: 323-442-4332; Fax: 323-442-4433; E-mail: juddrice{at}usc.edu.

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