Homologous Recombination at Human Centromeres: Friend or Foe?

DNA包含了细胞正常运作所需的一整套指令。在大多数情况下，人类细胞携带46个长DNA分子，每个分子都被打包成一个叫做染色体的结构。当一个细胞分裂成两个子细胞时，46条染色体被复制，这两个子细胞得到各自的副本是至关重要的。如果这种分离过程失败，子细胞可能会死亡、失灵，甚至有害，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中发现的一个独特的大区域，已知在确保染色体正确分离成两个子细胞方面起着至关重要的作用。着丝粒是由高度重复的DNA序列组成的，但我们仍然不知道为什么着丝粒包含这样的重复序列，以及为什么这对确保染色体正确分离很重要。研究这个问题将有助于我们理解细胞如何确保分离过程的准确性，并可能提出治疗由着丝粒缺陷引起的癌症的新方法。我的研究小组对一种称为同源重组（HR）的过程有着长期的兴趣。HR允许细胞使用类似的序列作为模板来修复DNA中的断裂。不过，人力资源部门偶尔也会犯错，造成额外的伤害。我们知道HR发生在着丝粒上，但尚不清楚这对着丝粒和染色体的正确分离是有益还是有害的影响。我们的初步结果表明，可能是前者。该项目的目标是了解HR如何协助着丝粒功能，以及参与HR的蛋白质如何防止潜在的有害后果。为此，我们将解决以下三个问题：HR的中心介质RAD51如何作用于人类着丝粒？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的调节剂如何作用于人类着丝粒？我们将重点了解两种蛋白质BRCA2和PALB2的作用，因为这两种蛋白质的缺陷会增加患癌症的风险。这将有助于我们了解BRCA2和PALB2是如何预防癌症发展的。3. 如何预防着丝粒HR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，这将使我们能够回答这些问题。我们将能够更好地理解HR如何作用于着丝粒，以及它如何保护细胞免受驱动癌症发展的染色体损失或获得。我们的研究还可能引导我们找到诊断癌症的新方法，并开发出新的治疗方法，这些方法可以与现有的治疗方法相结合，为患者提供更好的治疗效果。

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.