Every day, the DNA in every human cell suffers thousands of molecular injuries—broken strands, chemical alterations, misplaced letters—that must be repaired to prevent cancer and cell death. Researchers already know many of the proteins that fix this damage, but they do not fully understand how these proteins work together or how their failure makes tumours resistant to treatment. This project will use genome-wide CRISPR screens and chemical mutagenesis in mammalian cells to systematically map the genetic and functional relationships between DNA-repair genes. The team will also test how defects in these repair processes alter a cancer cell’s sensitivity to existing and experimental therapies. If successful, the work will produce a detailed wiring diagram of the DNA-damage response, revealing new targets for cancer drugs and explaining why some tumours stop responding to chemotherapy. This is fundamental science: it will not immediately change a patient’s treatment, but it will provide the mechanistic understanding needed to design smarter, more durable cancer therapies in the future.
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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.
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