DNA damage response mechanisms

DNA损伤是由与正常生活相关的内部DNA损伤剂（如氧气）和来自我们身体外部的试剂（如阳光和电离辐射）引起的。不修复由这些试剂引起的DNA损伤的后果是单个细胞的DNA序列变化的积累，这些变化可以重新编程细胞在不应该生长的时候生长。这种不受控制的细胞生长是所有癌症的基础。因此，我们了解细胞如何对DNA损伤做出反应以及如何修复这种损伤非常重要。使用单细胞（因此相对简单）酵母模型生物的工作在过去已经确定了许多DNA损伤反应途径，并导致了解这些功能如何修复DNA损伤并防止细胞在DNA受损时分裂。通过使用这些易于操作的酵母模型系统，科学家们已经能够定义DNA损伤反应途径所使用的许多基本分子机制，并在其他细胞过程的背景下检查这些功能。重要的是，虽然酵母相对简单，但它们处理这些问题的方式与人类细胞非常相似。很明显，多个相互依赖的DNA修复和信号通路可以防止突变发生，从而帮助我们避免癌症。在这项工作计划中，我建议研究DNA损伤反应途径如何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损伤的几个方面。我还建议探索DNA损伤反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DNA修复在预防突变方面同样重要。已知DNA损伤反应途径与DNA复制相互作用，以确保DNA损伤不会导致错误复制（即突变）。我建议主要使用酵母模型系统。然而，由于许多蛋白质和途径都在酵母和哺乳动物中发现，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。

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.