DNA damage response mechanisms

DNA损伤反应机制

• 批准号: G0600233/1
• 负责人: Antony Carr
• 金额: $ 266.71万
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0600233%2F1
• 关键词: DNA; damage; response; mechanisms

DNA damage is caused by both internal DNA damaging agents (like oxygen) that are associated with normal life and by agents from outside our bodies such as sunlight and ionising radiation. The consequences of not repairing the DNA damage caused by these agents is the accumulation of changes in the DNA sequence of individual cells that can reprogram the cell to grow when it should not be growing. Such uncontrolled cell growth is the basis of all cancers.It is therefore important that we understand how cells respond to DNA damage and how they repair such damage. Work using single celled (and thus relatively simple) yeast model organisms has in the past identified many DNA damage response pathways and lead to an understanding of how these function to both repair DNA damage and to prevent cells dividing when their DNA is damaged. By using these easily manipulated yeast model systems, scientists have been able to define many of the fundamental molecular mechanisms used by DNA damage response pathways and to examine these functions in the context of other cellular processes. Importantly, while yeasts are relatively simple, they use very similar ways of dealing with these problems as human cells do.It has become clear that multiple inter-dependent DNA repair and signalling pathways act to prevent mutations occurring and thus help us avoid cancer. In this program of work I propose to study several aspects of how DNA damage response pathways operate to control the production of other proteins in the cell and thus to help the cell tolerate and repair the DNA damage. I also propose to explore how the DNA damage response mechanisms interact with the process of replicating, or copying, the DNA. Accurate DNA replication is as important as DNA repair in preventing mutations. DNA damage response pathways are known to interact with DNA replication to ensure that DNA damage does not result in miscopying (i.e. mutation). I propose to largely use the yeast model systems. However, since many of the proteins and pathways involved are found both in the yeast and in mammals, I propose to extend specific studies into mammalian cells by using the mouse model system.

DNA损伤是由内部DNA损伤剂（如氧）引起的，与正常寿命以及来自阳光和电离辐射等体内外部的药物相关。不修复这些药物引起的DNA损伤的后果是单个细胞的DNA序列的变化积累，这些变化可以在不应生长时重新编程细胞生长。这种不受控制的细胞生长是所有癌症的基础。因此，重要的是，我们了解细胞如何应对DNA损伤以及它们如何修复这种损伤。过去使用单细胞（因此相对简单）酵母模型生物的工作鉴定了许多DNA损伤响应途径，并导致对这些功能如何修复DNA损伤的功能以及在DNA受损时如何划分细胞分裂。通过使用这些易于操纵的酵母模型系统，科学家能够定义DNA损伤响应途径使用的许多基本分子机制，并在其他细胞过程中检查这些功能。重要的是，尽管酵母菌相对简单，但它们使用非常相似的方法来处理这些问题，就像人类细胞一样。已经很清楚，多个相互依赖性的DNA修复和信号通路会起作用，以防止发生突变，从而帮助我们避免癌症。在这个工作计划中，我建议研究如何运作DNA损伤反应途径以控制细胞中其他蛋白质的产生，从而帮助细胞耐受和修复DNA损伤。我还建议探索DNA损伤响应机制如何与复制或复制DNA的过程相互作用。准确的DNA复制与预防突变中的DNA修复一样重要。已知DNA损伤响应途径与DNA复制相互作用，以确保DNA损伤不会导致失误（即突变）。我建议在很大程度上使用酵母模型系统。但是，由于在酵母和哺乳动物中都发现了许多所涉及的蛋白质和途径，因此我建议通过使用小鼠模型系统将特定的研究扩展到哺乳动物细胞中。