Abstract

The orchestration of DNA repair is of fundamental importance to the maintenance of genomic integrity and tumour suppression. DNA damage must be detected in the context of the varied chromatin landscape, its presence must be communicated throughout the cell to alter many ongoing processes, and the machinery that will mend the lesion must be recruited to the damage site. Our understanding of the pathways involved in the DNA damage response in human cells is often the result of pioneering studies in genetically-tractable organisms or through the identification of gene mutations causing genome instability syndromes. With the advent of CRISPR /Cas9-based gene editing, there is an opportunity to prospectively chart the response to DNA damage in human cells. During my presentation, I will present our efforts to map the genetic networks that govern the DNA damage response and will particularly discuss our work aimed at mapping the genetic architecture of the response to PARP inhibitors. Our work revealed new types of genetic vulnerabilities to PARP inhibition and in particular, I will discuss a type DNA lesion that could act as the elusive inhibited-PARP “trap”..