Chromosome Breaks and the DNA Damage Response in Transcribed Genes

DNA double-strand breaks (DSBs) can arise through normal DNA metabolism or through exposure to DNA damaging agents such as ionizing radiation (IR), and can lead to breaks in our chromosomes which store our genetic information. These lesions are normally repaired by one of two DSB repair pathways termed non-homologous end joining (NHEJ), or homologous recombination (HR) repair pathways. DSB repair is important as failure to repair such lesions can cause cell death, and their misrepair can trigger chromosomal rearrangements, which can lead to cancer. While considerable advances have been made in our understanding of DSB repair, how it occurs in the context of transcription, in which the genetic material within genes is copied into messenger RNA to facilitate protein production, is unclear. The aim of the proposed research is to understand how cells respond to chromosome breaks within transcribed genes and facilitate their accurate repair by homologous recombination. In particular, we will explore the roles of chromatin (structures in which DNA is wrapped up in) and the transcription machinery (which copies DNA into messenger RNA) in coordinating these responses. The proposed research will provide mechanistic insights into DSB detection and repair within transcribed genes, and further, how defects in these processes can be exploited to target particular cancers.