DNA damage response mechanisms

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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.