Bhadra Manika P, Horikoshi Nobuo, Pushpavallipvalli Sreerangam N C V L, Sarkar Arpita, Bag Indira, Krishnan Anita, Lucchesi John C, Kumar Rakesh, Yang Qin, Pandita Raj K, Singh Mayank, Bhadra Utpal, Eissenberg Joel C, Pandita Tej K
Indian Institute of Chemical Technology, Hyderabad, AP 500007, India.
Chromosoma. 2012 Feb;121(1):79-90. doi: 10.1007/s00412-011-0344-7. Epub 2011 Nov 10.
In Drosophila, males absent on the first (MOF) acetylates histone H4 at lysine 16 (H4K16ac). This acetylation mark is highly enriched on the male X chromosome and is required for dosage compensation in Drosophila but not utilized for such in mammals. Recently, we and others reported that mammalian MOF, through H4K16ac, has a critical role at multiple stages in the DNA damage response (DDR) and double-strand break repair pathways. The goal of this study was to test whether mof is similarly required for the response to ionizing radiation (IR) in Drosophila. We report that Drosophila mof mutations in males and females, as well as mof knockdown in SL-2 cells, reduce post-irradiation survival. MOF depletion in SL-2 cells also results in an elevated frequency of metaphases with chromosomal aberrations, suggesting that MOF is involved in DDR. Mutation in Drosophila mof also results in a defective mitotic checkpoint, enhanced apoptosis, and a defective p53 response post-irradiation. In addition, IR exposure enhanced H4K16ac levels in Drosophila as it also does in mammals. These results are the first to demonstrate a requirement for MOF in the whole animal IR response and suggest that the role of MOF in the response to IR is conserved between Drosophila and mammals.
在果蝇中，首个雄性缺失蛋白（MOF）可使组蛋白H4的赖氨酸16位点（H4K16ac）发生乙酰化。这种乙酰化标记在雄性果蝇的X染色体上高度富集，是果蝇剂量补偿所必需的，但在哺乳动物中并非如此。最近，我们和其他研究人员报道，哺乳动物的MOF通过H4K16ac在DNA损伤应答（DDR）和双链断裂修复途径的多个阶段发挥关键作用。本研究的目的是测试果蝇中mof对于电离辐射（IR）反应是否同样必需。我们报道，雄性和雌性果蝇中的mof突变以及SL-2细胞中的mof敲低都会降低辐射后的存活率。SL-2细胞中MOF的缺失还会导致染色体畸变的中期频率升高，这表明MOF参与了DDR。果蝇mof的突变还会导致有丝分裂检查点缺陷、凋亡增强以及辐射后p53反应缺陷。此外，与哺乳动物一样，IR照射也会提高果蝇中的H4K16ac水平。这些结果首次证明了在整个动物的IR反应中需要MOF，并表明MOF在IR反应中的作用在果蝇和哺乳动物之间是保守的。
