Homologous Recombination at Human Centromeres: Friend or Foe?

人类着丝粒的同源重组：是友还是敌？

• 批准号: MR/W017601/1
• 负责人: Fumiko Esashi
• 金额: $ 58.36万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW017601%2F1
• 关键词: Homologous; Recombination; Human; Centromeres; Friend

DNA contains the full set of instructions that cells need to function correctly. In most cases, human cells carry 46 long DNA molecules, each of which is packed into a structure called a chromosome. When a cell divides into two daughter cells, the 46 chromosomes are duplicated, and it is essential that the two daughter cells receive a copy of each. If this separation process fails, daughter cells may die, malfunction, or even become harmful, leading to various human diseases, most notably cancers.The centromere is a unique and large region found in each chromosome, known to play an essential role in ensuring that chromosomes are separated into the two daughter cells correctly. Centromeres are made of highly repetitive DNA sequences, but we still do not know why the centromere contains such repeats and why this is important in ensuring that chromosomes get separated correctly. Studying this problem will help us understand how cells ensure that this separation process is accurate, and may suggest new ways to treat cancers that are caused by centromere defects.My research group has a long-standing interest in a process called homologous recombination (HR). HR allows cells to fix breaks in their DNA, using similar sequences as a template. Occasionally though, HR can make mistakes, resulting in additional harmful damage. We know that HR happens at centromeres, but it is unclear whether this has a helpful or a harmful effect on centromeres and the correct separation of chromosomes. Our preliminary results suggest it may be the former. The goal of this project is to understand how HR assists centromere function, and how the proteins involved in HR prevent potentially harmful consequences. We will do this by addressing three questions:1. How does the central mediator of HR, called RAD51, act at human centromeres? This will help us understand in detail which properties of RAD51 are critical to normal centromere function. 2. How do the modulators of RAD51 act at human centromeres? We will focus on understanding the role of two proteins called BRCA2 and PALB2, because defects in these proteins increase the risk of developing cancers. This will help us understand how BRCA2 and PALB2 prevent cancer development. 3. How are the harmful effects of HR at centromeres prevented? Understanding this mechanism will help us predict the likelihood of cancer development. Our team has the expertise, equipment and collaborators that will allow us to answer these questions. We will be able to understand better how HR acts at centromeres and how it protects cells from the chromosome losses or gains that drive cancer development. Our research may also lead us to identify new ways to diagnose cancer and develop new therapeutics that can be used in combination with existing treatments to provide better outcomes for patients.

DNA包含细胞正常运作所需的全套指令。在大多数情况下，人类细胞携带46个长DNA分子，每个分子都被包装成一种称为染色体的结构。当一个细胞分裂成两个子细胞时，46条染色体被复制，这两个子细胞必须各自获得一份拷贝。如果这种分离过程失败，子代细胞可能会死亡、失灵，甚至变得有害，导致各种人类疾病，最明显的是癌症。着丝粒是在每条染色体上发现的一个独特的大区域，已知在确保染色体正确地分离到两个子代细胞方面发挥着至关重要的作用。着丝粒是由高度重复的DNA序列组成的，但我们仍然不知道着丝粒为什么包含这样的重复，以及为什么这对确保染色体正确分离是重要的。研究这个问题将有助于我们理解细胞如何确保这种分离过程的准确性，并可能提出治疗由着丝粒缺陷引起的癌症的新方法。我的研究小组长期以来一直对一种称为同源重组(HR)的过程感兴趣。HR允许细胞修复DNA的断裂，使用类似的序列作为模板。不过，人力资源部偶尔也会犯错误，导致额外的有害损害。我们知道HR发生在着丝粒上，但目前还不清楚这对着丝粒和染色体的正确分离有帮助还是有害的影响。我们的初步结果表明，可能是前者。这个项目的目标是了解HR如何协助着丝粒功能，以及HR中涉及的蛋白质如何防止潜在的有害后果。我们将通过解决三个问题来解决这一问题：1.人力资源的中央调节因子，称为RAD51，如何在人类着丝粒中发挥作用？这将有助于我们详细了解RAD51的哪些特性对正常着丝粒功能至关重要。2.RAD51的调节子是如何作用于人类着丝粒的？我们将重点了解两种名为BRCA2和PALB2的蛋白质的作用，因为这些蛋白质的缺陷会增加患癌症的风险。这将帮助我们了解BRCA2和PALB2是如何预防癌症发展的。3.如何预防HR对着丝粒的有害影响？了解这一机制将有助于我们预测癌症发展的可能性。我们的团队拥有专业知识、设备和合作者，将使我们能够回答这些问题。我们将能够更好地了解HR如何在着丝粒上发挥作用，以及它如何保护细胞免受推动癌症发展的染色体丢失或获得的影响。我们的研究还可能引导我们找到诊断癌症的新方法，并开发新的治疗方法，这些方法可以与现有的治疗方法结合使用，为患者提供更好的结果。

项目成果

Breaking the paradigm: early insights from mammalian DNA breakomes.

• DOI: 10.1111/febs.15849
• 发表时间: 2022-05
• 期刊: FEBS JOURNAL
• 影响因子: 5.4
• 作者: Saayman, Xanita;Esashi, Fumiko
• 通讯作者: Esashi, Fumiko