Break-Induced Replication: The Where, The Why, and The How

Break-induced replication (BIR) is a pathway that repairs one-ended double-strand breaks (DSBs). For decades, yeast model systems offered the only opportunities to study eukaryotic BIR. These studies described an unusual mode of BIR synthesis that is carried out by a migrating bubble and shows conservative inheritance of newly synthesized DNA, leading to genomic instabilities like those associated with cancer in humans. Yet, evidence of BIR functioning in mammals or during repair of other DNA breaks has been missing. Recent studies have uncovered multiple examples of BIR working in replication restart and repair of eroded telomeres in yeast and mammals, as well as some unexpected findings, including the RAD51 independence of BIR. Strong interest remains in determining the variations in molecular mechanisms that drive and regulate BIR in different genetic backgrounds, across organisms, and particularly in the context of human disease.