Centre for Chemical Biology, Indian Institute of Chemical Technology, Hyderabad 500607, India.
BMC Mol Biol. 2013 Jan 24;14:1. doi: 10.1186/1471-2199-14-1.
In Drosophila embryos, checkpoints maintain genome stability by delaying cell cycle progression that allows time for damage repair or to complete DNA synthesis. Drosophila MOF, a member of MYST histone acetyl transferase is an essential component of male X hyperactivation process. Until recently its involvement in G2/M cell cycle arrest and defects in ionizing radiation induced DNA damage pathways was not well established.
Drosophila MOF is highly expressed during early embryogenesis. In the present study we show that haplo-insufficiency of maternal MOF leads to spontaneous mitotic defects like mitotic asynchrony, mitotic catastrophe and chromatid bridges in the syncytial embryos. Such abnormal nuclei are eliminated and digested in the yolk tissues by nuclear fall out mechanism. MOF negatively regulates Drosophila checkpoint kinase 2 tumor suppressor homologue. In response to DNA damage the checkpoint gene Chk2 (Drosophila mnk) is activated in the mof mutants, there by causing centrosomal inactivation suggesting its role in response to genotoxic stress. A drastic decrease in the fall out nuclei in the syncytial embryos derived from mof¹/+; mnkp⁶/+ females further confirms the role of DNA damage response gene Chk2 to ensure the removal of abnormal nuclei from the embryonic precursor pool and maintain genome stability. The fact that mof mutants undergo DNA damage has been further elucidated by the increased number of single and double stranded DNA breaks.
mof mutants exhibited genomic instability as evidenced by the occurance of frequent mitotic bridges in anaphase, asynchronous nuclear divisions, disruption of cytoskeleton, inactivation of centrosomes finally leading to DNA damage. Our findings are consistent to what has been reported earlier in mammals that; reduced levels of MOF resulted in increased genomic instability while total loss resulted in lethality. The study can be further extended using Drosophila as model system and carry out the interaction of MOF with the known components of the DNA damage pathway.
在果蝇胚胎中，检查点通过延迟细胞周期进程来维持基因组稳定性，从而有时间进行损伤修复或完成 DNA 合成。果蝇 MOF 是 MYST 组蛋白乙酰转移酶的一个成员，是雄性 X 超激活过程的一个重要组成部分。直到最近，它在 G2/M 细胞周期阻滞和电离辐射诱导的 DNA 损伤途径缺陷中的作用还没有得到很好的证实。
果蝇 MOF 在胚胎早期高度表达。在本研究中，我们发现母体 MOF 的单倍不足导致有丝分裂缺陷，如有丝分裂不同步、有丝分裂灾难和染色单体桥在合胞胚胎中。这些异常核通过核脱落机制被消除和消化在卵黄组织中。MOF 负调控果蝇检查点激酶 2 肿瘤抑制同源物。在 DNA 损伤的情况下，检查点基因 Chk2（果蝇 mnk）在 mof 突变体中被激活，从而导致中心体失活，表明其在应对遗传毒性应激中的作用。mof¹/+;mnkp⁶/+ 雌性产生的合胞胚胎中脱落核的急剧减少进一步证实了 DNA 损伤反应基因 Chk2 的作用，以确保从胚胎前体池中清除异常核并维持基因组稳定性。mof 突变体经历 DNA 损伤的事实已经通过增加单链和双链 DNA 断裂的数量得到进一步阐明。
mof 突变体表现出基因组不稳定性，证据是后期有丝分裂中频繁出现的有丝分裂桥、核分裂不同步、细胞骨架破坏、中心体失活，最终导致 DNA 损伤。我们的发现与早期在哺乳动物中报道的一致，即 MOF 水平降低导致基因组不稳定性增加，而完全缺失则导致致死性。这项研究可以进一步扩展到使用果蝇作为模型系统，并进行 MOF 与已知 DNA 损伤途径成分的相互作用。
