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Regulation of DNA repair pathway choice during development

发育过程中 DNA 修复途径选择的调控

基本信息

批准号：
BB/H009957/1
负责人：
Nicholas Lakin
金额：
$ 69.61万
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：
2010
资助国家：
英国
起止时间：
2010 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FH009957%2F1
关键词：
Regulation DNA repair pathway choice

项目摘要

The genetic code (DNA) contains a blueprint to produce all the machinery required for a cell to perform its various functions in a programmed manner. Preservation of this code is critical to maintain normal cellular functions. However, DNA is under continual attack from agents that cause changes in the genetic code. This can occur when cells copy their DNA (DNA replication), through changes in the sequence of DNA building blocks (mutation), or by creating breaks in the DNA molecule. Interestingly, DNA damage also occurs in a tightly regulated context during a number of normal cellular processes including development of the immune-system and transfer of genetic information as cells segregate their genomes in a process know as meiosis. Therefore, cells have developed a complex network of pathways to detect DNA damage when it occurs and correct these faults by DNA repair. The importance of DNA repair is underscored by the observations that defects in these pathways leads to a variety of debilitating clinical symptoms including premature ageing, immune-system failure, developmental abnormalities and increased cancer risk. Therefore, understanding DNA repair will provide insights into several fundamental biological processes in addition to clues regarding the molecular basis of a number of disease states. Breaks in both strands of the DNA double helix (double strand breaks; DSBs) are one of the most toxic varieties of DNA damage. These can be repaired by directly re-joining DNA breaks (non-homologous end-joining; NHEJ), or by using homologous DNA as a template to restore genome integrity (homology-directed repair; HDR). The components of these two pathways are well characterised. However, the factors that influence whether cells repair damage by NHEJ or HDR remains relatively ill defined. Defects in DNA repair lead to a variety of developmental abnormalities including defective antibody production, cranial-facial abnormalities and degeneration of the nervous system. Despite this, how these pathways are regulated as multi-cellular organisms develop into a variety of specialised tissues remains largely unexplored. DNA repair is achieved by similar mechanisms in all organisms from bacteria to humans. Therefore, studying these pathways in relatively simple model organisms has increased our understanding of how these processes work in humans. Unfortunately, certain commonly used model organisms lack key components of human DNA DSB repair pathways and do not undergo a developmental program into specialised cell types. In contrast, the soil dwelling amoeba Dictyostelium is an easily grown and manipulated organism that undergoes a relatively simple developmental program. As such, it is a commonly used model to study cell type specification and differentiation. In addition, our previous work has illustrated that DNA DSB repair pathways in this organism are more similar to humans than other commonly used model organisms. The aims of this research are to exploit these observations and use Dictyostelium as a model to study how DNA DSB repair pathway choice is regulated in the context of an organism's life cycle and developmental program. In addition to providing insights into how DNA repair pathways are regulated in Dictyostelium, these studies will likely be applicable to how these processes are achieved in other higher organisms including humans.

遗传密码 (DNA) 包含一个蓝图，用于产生细胞以编程方式执行其各种功能所需的所有机制。保存该代码对于维持正常的细胞功能至关重要。然而，DNA 不断受到导致遗传密码变化的因素的攻击。当细胞通过改变 DNA 构建模块的序列（突变）或在 DNA 分子中产生断裂来复制其 DNA（DNA 复制）时，就会发生这种情况。有趣的是，在许多正常细胞过程中，DNA损伤也会在严格调控的环境中发生，包括免疫系统的发育和细胞在减数分裂过程中分离其基因组时遗传信息的转移。因此，细胞已经形成了一个复杂的通路网络，可以在 DNA 损伤发生时进行检测，并通过 DNA 修复来纠正这些错误。观察结果强调了 DNA 修复的重要性，即这些途径的缺陷会导致各种使人衰弱的临床症状，包括过早衰老、免疫系统衰竭、发育异常和癌症风险增加。因此，了解 DNA 修复除了提供有关多种疾病状态的分子基础的线索外，还将深入了解几种基本的生物过程。 DNA 双螺旋双链断裂（双链断裂；DSB）是最具毒性的 DNA 损伤之一。这些可以通过直接重新连接 DNA 断裂（非同源末端连接；NHEJ）或使用同源 DNA 作为模板来恢复基因组完整性（同源定向修复；HDR）来修复。这两条途径的组成部分已得到很好的表征。然而，影响细胞是否通过 NHEJ 或 HDR 修复损伤的因素仍然相对不明确。 DNA 修复缺陷会导致多种发育异常，包括抗体产生缺陷、颅面部异常和神经系统退化。尽管如此，当多细胞生物发育成各种专门组织时，这些途径是如何受到调节的仍然很大程度上未被探索。从细菌到人类的所有生物体中，DNA 修复都是通过类似的机制实现的。因此，在相对简单的模型生物体中研究这些途径增加了我们对这些过程如何在人类中发挥作用的理解。不幸的是，某些常用的模型生物体缺乏人类 DNA DSB 修复途径的关键成分，并且不经历特殊细胞类型的发育程序。相比之下，居住在土壤中的变形虫盘基网柄菌是一种易于生长和操纵的生物体，其发育程序相对简单。因此，它是研究细胞类型规范和分化的常用模型。此外，我们之前的工作表明，与其他常用的模型生物体相比，该生物体中的 DNA DSB 修复途径与人类更相似。本研究的目的是利用这些观察结果并使用盘基网柄菌作为模型来研究 DNA DSB 修复途径选择如何在生物体生命周期和发育程序的背景下受到调节。除了深入了解盘基网柄菌中 DNA 修复途径的调控方式外，这些研究还可能适用于包括人类在内的其他高等生物体中如何实现这些过程。