HMOF histone acetyltransferase is required for histone H4 lysine 16 acetylation in mammalian cells
HMOF histone acetyltransferase is required for histone H4 lysine 16 acetylation in mammalian cells
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DOI：
10.1128/mcb.25.15.6798-6810.2005
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发表时间：
2005-08-01
影响因子：
5.3
通讯作者：
Akhtar, A
中科院分区：
文献类型：
--
作者：
Taipale, M;Rea, S;Akhtar, A
可逆组蛋白乙酰化在染色质结构和功能的调节中起着重要作用。在这里，我们报告了果蝇黑腹果蝇MOF的人类同源基因，hMOF，是一个组蛋白H4赖氨酸K16特异的乙酰转移酶。在哺乳动物细胞中，hMOF也是这种修饰所必需的。通过Western印迹分析和内源性组蛋白的质谱分析发现，在HeLa和HepG2细胞中敲除hMOF导致组蛋白H4K16乙酰化显著减少。我们还提供了证据，类似于果蝇的剂量补偿系统，hMOF和hMSL3在哺乳动物细胞中形成一个复合体。HMOF和hMSL3小干扰RNA处理的细胞也表现出显著的核形态变形，表现为多叶状核表型。RNA干扰降低HeLa细胞hMOF蛋白水平。细胞也会导致细胞在细胞周期的G(2)和M期积累。用DNA损伤反应通路的特定抑制剂治疗可以逆转hMOF蛋白水平降低引起的细胞周期停滞。此外，hMOF耗竭的细胞显示出更多的磷酸化ATM和伽马H_2AX焦点，并且对电离辐射的修复反应受损。综上所述，我们的数据表明hMOF是哺乳动物细胞中组蛋白H4赖氨酸16乙酰化所必需的，并提示hMOF在细胞周期进程中的DNA损伤反应中发挥作用。
Reversible histone acetylation plays an important role in regulation of chromatin structure and function. Here, we report that the human orthologue of Drosophila melanogaster MOF, hMOF, is a histone H4 lysine K16-specific acetyltransferase. hMOF is also required for this modification in mammalian cells. Knockdown of hMOF in HeLa and HepG2 cells causes a dramatic reduction of histone H4K16 acetylation as detected by Western blot analysis and mass spectrometric analysis of endogenous histones. We also provide evidence that, similar to the Drosophila dosage compensation system, hMOF and hMSL3 form a complex in mammalian cells. hMOF and hMSL3 small interfering RNA-treated cells also show dramatic nuclear morphological deformations, depicted by a polylobulated nuclear phenotype. Reduction of hMOF protein levels by RNA interference in HeLa. cells also leads to accumulation of cells in the G(2) and M phases of the cell cycle. Treatment with specific inhibitors of the DNA damage response pathway reverts the cell cycle arrest caused by a reduction in hMOF protein levels. Furthermore, hMOF-depleted cells show an increased number of phospho-ATM and gamma H2AX foci and have an impaired repair response to ionizing radiation. Taken together, our data show that hMOF is required for histone H4 lysine 16 acetylation in mammalian cells and suggest that hMOF has a role in DNA damage response during cell cycle progression.