New mechanistic insights into DNA repair by non-homologous end-joining
DNA double-strand breaks are highly toxic DNA lesions that can lead to cell death or genome instability and cancer if they are not repaired in an error-free way. Most DNA double-strand breaks in human cells are repaired by a process called non-homologous end-joining (NHEJ). This pathway involves initial processing and eventual re-ligation of the broken DNA ends by a variety of different proteins and enzymatic activities in a tightly controlled manner. While NHEJ is required for maintenance of genome stability in all cells, it plays a particularly important role in developing lymphocytes, because programmed DNA double-strand breaks are generated at immune receptor loci to generate antibody diversity. During my talk, I will discuss our recent identification of PAXX, a previously uncharacterised factor that plays a key role in DNA repair by NHEJ. I will describe how, using structural biology, biochemistry and cell biology approaches, we have found that PAXX most likely acts as a molecular lock to hold together two broken DNA ends to promote repair of a double-strand break. The implications this has for our current understanding of how cells repair DNA by NHEJ will also be discussed.