Interdomain crosstalk in MORC3

项目摘要 微小病原体3(MORC3)与癌症相关的炎症有关。近期 我们小组的研究表明，唐氏综合症患者MORC3基因的表达水平降低 综合征(DS)，然而MORC3在疾病或正常细胞过程中的确切作用 人们对此仍然知之甚少。我们的初步数据显示MORC3有一种固有的ATPase 活性以及催化的ATPase结构域与DNA结合，而相邻的Cw结构域 识别组蛋白H3并调节MORC3的ATPase活性。分子 MORC3的这些新功能背后的机制尚不清楚，将在 建议进行的研究。我们推测DNA刺激的MORC3的ATPase活性是 通过MORC3中不活跃的CW结构域的组蛋白结合活性来介导 状态，与ATPase结构域结合并自动抑制；以及组蛋白H3 PTMS改变结合 并微调MORC3的ATPase活性。我们的目标是定义分子基础和 MORC3与染色质多价结合的功能意义 了解其自动调节的机制。通过确定生物角色和 获得机制细节后，我们将了解这种基本的染色质重塑是如何 组件是可以控制的。 在这项研究中，我们将采用体外和体内方法的强大组合。 研究一种新发现的表观遗传调控机制。我们集成了X射线 结晶学，先进的Förster共振能量转移，核磁共振波谱和高分辨 通过分子和细胞生物学工具进行技术实验，以深入了解 ATPase和Cw结构域在MORC3生物学活性中的作用。 深入研究MORC3的结构、生化和功能 染色质重塑对染色质生物学和基础分子生物学的重要影响 酵素。它还将有助于我们理解表观遗传驱动的信号事件 在DS和其他人类疾病中放松管制。

Project Summary Microrchidia 3 (MORC3) has been linked to cancer-associated inflammations. Recent studies from our group demonstrate that MORC3 is deregulated in patients with Down syndrome (DS), however the precise role of MORC3 in disease or in normal cellular processes remains poorly understood. Our preliminary data show that MORC3 has an intrinsic ATPase activity and that the catalytic ATPase domain binds to DNA, whereas the adjacent CW domain recognizes histone H3 and mediates the ATPase activity of MORC3. The molecular mechanisms underlying these novel functions of MORC3 are unclear and will be elucidated in the proposed studies. We hypothesize that the DNA-stimulated ATPase activity of MORC3 is mediated through histone-binding activity of the CW domain, which in the MORC3 inactive state, binds to and autoinhibits the ATPase domain; and that PTMs of histone H3 alter binding of CW and fine-tune the ATPase activity of MORC3. We aim to define the molecular basis and functional significance of the multivalent engagement of MORC3 with chromatin and to understand the mechanism of its autoregulation. By establishing the biological role and obtaining the mechanistic details, we will learn how this fundamental chromatin remodeling component can be controlled. In this research we will employ a powerful combination of in vitro and in vivo approaches to examine a newly identified epigenetic regulatory mechanism. We integrate X-ray crystallographic, advanced Förster Resonance Energy Transfer, NMR spectroscopic and high- throughput technological experiments with molecular and cell biology tools to gain insight into the role of the ATPase and CW domains in biological activities of MORC3. In-depth structural, biochemical and functional characterization of MORC3 will have significant impact on chromatin biology and basic molecular biology of chromatin-remodeling enzymes. It will also aid to our understanding of the epigenetic-driven signaling events that are deregulated in DS and other human diseases.