Homologous recombination in mammalian cells: From molecular mechanisms to pathology

Abstract Homologous recombination (HR) is an evolutionarily conserved process that is essential for genome plasticity and is thus involved in numerous fundamental biological processes. This chapter summarizes the HR molecular mechanisms in mammals, its roles in DNA double-strand break (DSB) repair and reactivation of arrested replication forks, and the consequences of dysregulation of these processes in human pathologies. HR competes with other pathways of DSB repair; we propose a two-step model for the DSB repair pathway selection. HR is a double-edged sword that favors genome stability maintenance but can generate genome instability. We discuss situations of HR-induced genetic instability and strategies developed to protect against excessive HR, including regulation of the cell cycle, detoxification of HR intermediates, and repression of HR initiation. Then, we discuss HR dysregulation in tumors and anticancer strategies targeting HR. Finally, we discuss the roles of HR in the molecular evolution of the genome.