Structure and function of chromatin remodelling ATPase's and their dysfunction in in human disease.

染色质重塑 ATP 酶的结构和功能及其在人类疾病中的功能障碍。

• 批准号: MR/S021647/1
• 负责人: Tom Owen-Hughes
• 金额: $ 157.09万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS021647%2F1
• 关键词: Structure; function; chromatin; remodelling; ATPase

The genomes of eukaryotes are associated with histone proteins to form a DNA protein complex called chromatin. The regulation of chromatin structure provides one means by which eukaryotic organisms regulated access to DNA. One means by which this is achieved involves the action of an extended family molecular motor proteins, known as chromatin remodelling ATPases. Recent advances to electron microscopy provide an opportunity to gain major new insights into how these motor proteins interact with chromatin. In this proposal we will apply advanced electron microscopy and image processing together with other complementary techniques to study how the shape of these motor proteins changes as they act to reconfigure chromatin. This will provide new insight into the process by which access to genes is regulated. It has recently become apparent that the genes that encode these motor proteins are often altered in cancer cells. We have noticed that these alterations repeatedly occur at a similar position on several different subtypes of motor proteins. Related alterations are also detected in some congenital diseases. As a result, we will systematically characterise how these alterations affect the way the motors work and determine which stage in the motors activity is blocked. We will also generate cell lines that will enable us to study the difference in between the loss of genes that encode motor proteins and the repeated alterations that are observed in cancers. We will find out whether cells are able to function normally when an altered copy of the motor gene is removed. If this is the case, blocking the altered motor and letting the cells carry on using the normal copy of the motor gene they typically retain may provide a way of treating patients. The proposal will generate a platform of knowledge from which new ways to target the defective motors can be devised.

真核生物的基因组与组蛋白结合形成一种称为染色质的DNA蛋白复合物。染色质结构的调节提供了真核生物调节DNA进入的一种手段。实现这一点的一种方法涉及一个大家族分子马达蛋白的作用，称为染色质重塑ATP酶。电子显微镜的最新进展提供了一个机会，以获得这些马达蛋白如何与染色质相互作用的主要新见解。在这项提案中，我们将应用先进的电子显微镜和图像处理以及其他互补技术来研究这些马达蛋白的形状如何改变，因为它们的行为来重新配置染色质。这将提供新的见解的过程中，获得基因的调控。最近发现，编码这些马达蛋白的基因在癌细胞中经常发生改变。我们注意到，这些改变重复发生在几种不同亚型的马达蛋白的相似位置。在一些先天性疾病中也检测到相关的改变。因此，我们将系统地分析这些改变如何影响运动的工作方式，并确定运动活动的哪个阶段被阻断。我们还将产生细胞系，使我们能够研究编码运动蛋白的基因的丢失与在癌症中观察到的重复改变之间的差异。我们将发现当运动基因的一个改变的拷贝被移除时，细胞是否能够正常运作。如果是这样的话，阻断改变的运动，让细胞继续使用它们通常保留的运动基因的正常拷贝，可能会提供一种治疗患者的方法。该提案将产生一个知识平台，从中可以设计出针对有缺陷电机的新方法。

项目成果

Proteomic profiling reveals distinct phases to the restoration of chromatin following DNA replication

• DOI: 10.1016/j.celrep.2023.111996
• 发表时间: 2023-01-20
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Alvarez, Vanesa;Bandau, Susanne;Alabert, Constance
• 通讯作者: Alabert, Constance

Chromatin remodelling comes into focus.

• DOI: 10.12688/f1000research.21933.1
• 发表时间: 2020-01-01
• 期刊: F1000Research
• 作者: Sundaramoorthy, Ramasubramian;Owen-Hughes, Tom
• 通讯作者: Owen-Hughes, Tom

The Face of Chromatin Variants.

染色质变异的面孔。

• DOI: 10.1016/j.cell.2019.08.024
• 发表时间: 2019
• 期刊: Cell
• 影响因子: 64.5
• 作者: Flaus A

Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for activation and repression of transcription.

• DOI: 10.1016/j.celrep.2021.109943
• 发表时间: 2021-11-02
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Blümli S;Wiechens N;Wu MY;Singh V;Gierlinski M;Schweikert G;Gilbert N;Naughton C;Sundaramoorthy R;Varghese J;Gourlay R;Soares R;Clark D;Owen-Hughes T
• 通讯作者: Owen-Hughes T