Understanding the role of chromatin remodelling in telomere maintenance

了解染色质重塑在端粒维持中的作用

• 批准号: BB/M008142/1
• 负责人: Helder Ferreira
• 金额: $ 56.82万
• 依托单位: University of St Andrews
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM008142%2F1
• 关键词: Understanding; role; chromatin; remodelling; telomere

Our chromosomes are long linear pieces of DNA and, just like any thread, the ends of chromosomes (termed telomeres) are fragile and prone to fraying. Telomeres consist of specific DNA sequences and associated binding proteins that protect chromosomes from DNA damage. One of the main factors that affect DNA damage and repair is the chromatin context within which the DNA damage occurs. Chromatin is the native form that all eukaryotic genomes are found as; not as naked DNA but rather as a combination of DNA with proteins that compacts genomic DNA to fit into the nucleus. Chromatin has a profound effect on all processes that require access to genomic DNA. Therefore the cell has developed means of regulating chromatin structure. One of the most important of these is the action of ATP-dependent chromatin remodelling enzymes (Snf2 proteins). These Snf2 enzymes use the energy from ATP hydrolysis to change chromatin structure and thereby alter the accessibility of the underlying DNA.Snf2 proteins are known to regulate DNA repair throughout chromosomes. However, their function at telomeres is much less understood. This is important to address as mutations in some Snf2 proteins are linked to inappropriate DNA repair at telomeres that define a subset of human cancers. Therefore, we need to understand the nature of chromatin remodelling at telomeres and how this affects DNA repair. This is a complex topic and therefore our best chance of understanding the underlying mechanisms lie in studying model organisms with simplified DNA repair and chromatin remodelling pathways. We will use budding yeast, a single-celled eukaryote that for many years has pioneered our understanding of how chromatin affects DNA repair. The budding yeast Snf2 protein Uls1 was recently found to bind telomeres and its deletion results in telomere fusions (a type of inappropriate DNA repair). Our research will address how Uls1 works, what its remodelling and why this affects telomeres. An additional aspect of Uls1 that makes it worthy of study is its connection to SUMO (Small Ubiquitin-like modifier). Cells commonly use the attachment of reversible marks (post-translational modifications) to proteins as molecular switches and SUMO is one such modification. However, in the context of DNA damage, SUMO is particularly important as it regulates DNA repair processes. How Uls1 co-ordinates chromatin remodelling with changes in sumoylation status may reveal novel insight into telomeres and DNA repair. This work will begin to answer fundamental questions about the nature of chromatin remodelling at telomeres: a basic biological problem. It will also lay the foundation for future research into the links between chromatin remodelling, SUMO modification and telomere maintenance that may have translational impact.

我们的染色体是长长的线性DNA片段，就像任何线一样，染色体的末端（称为端粒）是脆弱的，容易磨损。端粒由特定的DNA序列和保护染色体免受DNA损伤的相关结合蛋白组成。影响DNA损伤和修复的主要因素之一是DNA损伤发生的染色质环境。染色质是所有真核生物基因组的天然形式;不是裸露的DNA，而是DNA与蛋白质的组合，将基因组DNA压缩以适应细胞核。染色质对所有需要获取基因组DNA的过程都有深远的影响。因此，细胞已经发展出调节染色质结构的手段。其中最重要的是ATP依赖性染色质重塑酶（Snf 2蛋白）的作用。这些Snf 2酶利用ATP水解产生的能量来改变染色质结构，从而改变潜在DNA的可及性。已知Snf 2蛋白在整个染色体中调节DNA修复。然而，它们在端粒中的功能却鲜为人知。这一点很重要，因为一些Snf 2蛋白的突变与端粒上不适当的DNA修复有关，而端粒定义了人类癌症的一个子集。因此，我们需要了解端粒染色质重塑的性质以及这如何影响DNA修复。这是一个复杂的话题，因此我们了解潜在机制的最佳机会在于研究具有简化的DNA修复和染色质重塑途径的模式生物。我们将使用芽殖酵母，这是一种单细胞真核生物，多年来一直是我们了解染色质如何影响DNA修复的先驱。最近发现芽殖酵母Snf 2蛋白Uls 1结合端粒，其缺失导致端粒融合（一种不适当的DNA修复）。我们的研究将解决Uls 1如何工作，它的重塑以及为什么会影响端粒。Uls 1的另一个值得研究的方面是它与SUMO（小泛素样修饰物）的联系。细胞通常使用可逆标记（翻译后修饰）附着到蛋白质上作为分子开关，SUMO就是这样一种修饰。然而，在DNA损伤的背景下，SUMO特别重要，因为它调节DNA修复过程。Uls 1如何协调染色质重塑与sumoylation状态的变化可能揭示端粒和DNA修复的新见解。这项工作将开始回答关于染色体端粒重塑的本质的基本问题：一个基本的生物学问题。这也将为将来研究染色质重塑，SUMO修饰和端粒维持之间的联系奠定基础，这些联系可能具有翻译影响。

项目成果

The ATP-dependent chromatin remodelling enzyme Uls1 prevents Topoisomerase II poisoning

• DOI: 10.1101/412783
• 发表时间: 2018-09
• 期刊: Nucleic Acids Research
• 影响因子: 14.9
• 作者: A. Swanston;Katerina Zabrady;Helder C. Ferreira

The ATP-dependent chromatin remodelling enzyme Uls1 prevents Topoisomerase II poisoning.

ATP 依赖性染色质重塑酶 Uls1 可预防拓扑异构酶 II 中毒。

• DOI: 10.1093/nar/gkz362
• 发表时间: 2019
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Swanston A