A new molecular scissors involved in DNA repair

Our chromosomes are frequently subjected to insults that damage DNA, and if not rectified the resulting DNA lesions can cause mutations and human disease. Nucleases play vitally important roles in signaling and repairing DNA damage. They also play critically important roles in processing and repairing replication forks that collapse or break. The ability of nucleases to recognize and cleave specific structures arising at stalled forks is essential for protecting and repairing these forks and for allowing DNA replication to continue. However, it is important that the activity of structure-specific nucleases is kept in check to prevent inappropriate genome cleavage that would result in genome instability and disease. This is achieved, at least in part, by tight regulation of nuclease access to chromatin. The project on offer will use cutting edge technologies, including genome editing, to investigate the roles and regulation of a poorly characterized nuclease frequently mutated in cancers. We recently found that the nuclease in question is recruited to DNA damage sites in an unusual way and we would like to understand the underlying mechanisms in detail. We are particularly keen to understand how pathological mutations in the mysterious factor derail cell function in a way that causes cancer.