Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining

Non-homologous end joining (NHEJ) is one of the two principal damage repair pathways for DNA double-strand breaks in cells. In this review, we give a brief overview of the system including a discussion of the effects of deregulation of NHEJ components in carcinogenesis and resistance to cancer therapy. We then discuss the relevance of targeting NHEJ components pharmacologically as a potential cancer therapy and review previous approaches to orthosteric regulation of NHEJ factors. Given the limited success of previous investigations to develop inhibitors against individual components, we give a brief discussion of the recent advances in computational and structural biology that allow us to explore different targets, with a particular focus on modulating protein–protein interaction interfaces. We illustrate this discussion with three examples showcasing some current approaches to developing protein–protein interaction inhibitors to modulate the assembly of NHEJ multiprotein complexes in space and time.