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The Mammalian Ortholog of Drosophila MOF That Acetylates Histone H4 Lysine 16 Is Essential for Embryogenesis and Oncogenesis

Arun Gupta,^1, T. Geraldine Guerin-Peyrou,^2, Girdhar G. Sharma,^1, Changwon Park,¹ Manjula Agarwal,¹ Ramesh K. Ganju,³ Shruti Pandita,¹ Kyunghee Choi,¹ Saraswati Sukumar,⁴ Raj K. Pandita,¹ Thomas Ludwig,^2* and Tej K. Pandita^1*

Washington University School of Medicine, Saint Louis, Missouri 63108,¹ Institute of Cancer Genetics, Columbia University, New York, New York 10032,² Harvard Medical School, Boston, Massachusetts 02115,³ John Hopkins School of Medicine, Baltimore, Maryland 21231⁴

Received 13 June 2007/ Returned for modification 16 July 2007/ Accepted 11 October 2007

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 human MOF (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 to ionizing radiation (IR). Here we show that MOF plays an essential role in mammals during embryogenesis and oncogenesis. Ablation of the mouse Mof gene (mMof) 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 and primary tumors demonstrated similar or elevated hMOF and H4K16ac levels. Accordingly, MOF overexpression 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 and oncogenesis and that MOF is an essential factor for embryogenesis and oncogenesis.

Published ahead of print on 29 October 2007.

These authors contributed equally.