Pro and Anti-Mutagenic Function of DNA Damage Tolerance in the Mammalian System

The origin of cancer lies in the genetic code (DNA) and in the cell's (in) ability to keep this error-free. Due to influences from both outside and inside the body, the genetic code of cells can be damaged, and many processes have evolved to repair this damage. Unfortunately, these processes can make mistakes, leaving mutations in the DNA. As the DNA acts as a blueprint (genes) for how the cells should operate and how the machinery of the cells should be made, these mutations can cause disruptions in this process. When mutations happen in genes that are responsible for regulating cell duplication, the cell can lose control of this process. This causes rapid division of these cells, often leading to more mistakes being made and further dysregulating cell division. Finally, this deregulated cell growth can lead to the formation of cancer. Besides the prevention of DNA damage, the best way for a cell to avert turning cancerous is the accurate repair of the damage. The pathways responsible for this are complex, and many questions remain about their exact mode of operation, which proteins are involved, how they are initialized, processed, and what the consequences are. Knowing how these processes work will push forward our understanding of both basic biology, tumorigenesis and benefit cancer therapy with DNA damaging agents. Many of the classical chemotherapeutics work on the principle that tumor cells divide rapidly and that the DNA repair pathways are compromised. By introducing a high amount of DNA damage, these cells will not be able to repair the damage in time and die, while normal cells have more time and are better equipped to remove the damage. By gaining a better understanding of the repair processes, different specific inhibitors or types of damage can be applied to combat cancer more effectively. In this thesis, we investigate a specific activity within the DNA damage response network that prevents the detrimental effect of DNA lesions predominantly during replication. This system, known as DNA damage ...