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Mol. Cell. Biol. doi:10.1128/MCB.01045-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Mammalian Ortholog of Drosophila MOF that Acetylates Histone H4 Lysine16 is Essential for Embryogenesis and Oncogenesis

Washington University School of Medicine, Saint Louis, MO 63108; College of Physicians and Surgeons, Columbia University, New York, NY 10032, Harvard Medical School, Boston, MA 02115, John Hopkins School of Medicine, Baltimore, MD 21231, USA

^* To whom correspondence should be addressed. Email: TL54{at}columbia.edu. pandita{at}wustl.edu.

	Abstract

The mammalian ortholog of the Drosophila MOF (males absent on the first) gene product is a histone H4 lysine 16-specific acetyltransferase. Recent studies have shown that depletion of hMOF in human cell lines leads to genomic instability, spontaneous chromosomal aberrations, cell cycle defects, altered nuclear morphology, reduced transcription of certain genes and defective DNA damage response (DDR) to ionizing radiation (IR). Here we show that MOF plays an essential role in mammals during embryogenesis and oncogenesis. Ablation of the mouse Mof (mMof) gene by gene targeting resulted in early embryonic lethality and cell death. Lethality correlated with the loss of H4 lysine 16 acetylation (H4K16ac), and could not be rescued by concomitant inactivation of ATM or p53. In comparison to primary cells or normal tissue, all immortalized human normal and tumor cell lines, as well as, primary tumors demonstrated similar or elevated hMOF and H4K16ac levels. Accordingly, MOF over expression correlated with increased cellular proliferation, oncogenic transformation and tumor growth. Thus, these data reveal that the acetylation of histone H4 at K16 by MOF is an epigenetic signature of cellular proliferation common to both embryogenesis as well as oncogenesis and MOF is an essential factor for embryogenesis and oncogenesis.

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• Thomas, T., Dixon, M. P., Kueh, A. J., Voss, A. K. (2008). Mof (MYST1 or KAT8) Is Essential for Progression of Embryonic Development Past the Blastocyst Stage and Required for Normal Chromatin Architecture. Mol. Cell. Biol. 28: 5093-5105 [Abstract] [Full Text]