Abstract
Understanding what drives the choice between homologous recombination (HR) and non-homologous end joining (NHEJ) as the DNA double-strand break (DSB) repair pathway can help elucidate genome repair mechanisms and acquired drug resistance in cancer cells. This choice is closely linked to the highly regulated process of DNA end resection, mediated by several nucleases. Many laboratories have identified several factors involved in DNA end resection, but we are only beginning to appreciate the mechanisms that underpin DSB repair pathway choice. In this Review, we highlight how DSB repair factors, DSB repair regulators, and chromatin modifications determine whether HR or NHEJ is engaged, focusing on the antagonistic roles of the tumor suppressor complex BRCA1–BARD1 and the 53BP1 axis in repair pathway choice. How RNA–DNA hybrids affect HR execution and how they are processed by helicases and HR factors is also discussed. Moreover, we describe how dysfunction in repair pathway choice affects tumorigenesis and drives chemotherapeutic resistance.