The mammalian ortholog of Drosophila MOF that acetylates histone H4 lysine 16 is essential for embryogenesis and oncogenesis
The mammalian ortholog of Drosophila MOF that acetylates histone H4 lysine 16 is essential for embryogenesis and oncogenesis
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DOI：
10.1128/mcb.01045-07
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发表时间：
2008-01-01
影响因子：
5.3
通讯作者：
Pandita, Tej K.
中科院分区：
文献类型：
--
作者：
Gupta, Arun;Guerin-Peyrou, T. Geraldine;Pandita, Tej K.
果蝇MOF基因产物的哺乳动物直系同源物（第一个基因上没有雄性）是组蛋白H4赖氨酸16特异性乙酰转移酶。最近的研究表明，人细胞系中人MOF（hMOF）的缺失导致基因组不稳定性、自发染色体畸变、细胞周期缺陷、改变的核形态、某些基因的转录减少以及对电离辐射（IR）的缺陷性DNA损伤反应。在这里，我们表明，MOF在哺乳动物胚胎发生和肿瘤发生中起着至关重要的作用。通过基因靶向切除小鼠Mof基因（mMof）导致早期胚胎致死和细胞死亡。致死率与H4赖氨酸16乙酰化（H4K16ac）的损失相关，并且不能通过ATM或p53的伴随失活来挽救。与原代细胞或正常组织相比，所有永生化人正常和肿瘤细胞系以及原代肿瘤均表现出相似或升高的hMOF和H4K16ac水平。因此，MOF过表达与增加的细胞增殖、致癌转化和肿瘤生长相关。因此，这些数据表明，组蛋白H4在K16处被MOF乙酰化是胚胎发生和肿瘤发生共同的细胞增殖的表观遗传特征，并且MOF是胚胎发生和肿瘤发生的必要因素。
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.