Genetic and functional interactions in the mammalian DNA-damage response (360G-Wellcome-206388_Z_17_Z)

DNA in our cells is frequently subject to a wide array of molecularly-distinct forms of damage. To cope with this, life has evolved multiple DNA repair and associated processes, collectively termed the DNA-damage response (DDR). While considerable progress has been made in identifying DDR proteins and their regulators, much remains to be learned about how they operate and are controlled. Building on our successful proof-of-concept studies, we will carry out genome-wide and focused genetic screens via state-of-the-art CRISPR-Cas9 approaches and haploid-cell based chemical mutagenesis. Together with ensuing validation and mechanistic studies, the proposed research has the following interconnected goals: To identify novel genetic and functional relationships between DDR genes/proteins, and between these and other cellular components, thereby providing fundamental insights into how mammalian cells respond to DNA damage and defining how such responses are controlled and coordinated. To establish how defects and deregulation of certain DDR processes affect cellular sensitivity and resistance to established and emerging cancer therapies, and to explore the potential clinical relevance of these affects. To expand our knowledge of how DDR processes are affected by protein post-translational modifications, particularly ubiquitylation and phosphorylation.