Mechanisms and Consequences of Break-Induced Replication

Abstract

Homology-dependent repair of chromosomal double-strand breaks (DSBs) usually involves short tracts of DNA synthesis. However, repair of DSBs that have only one end with homology to a donor chromosome can occur by extensive DNA synthesis from the site of strand invasion to the telomere, a process referred to as break-induced replication (BIR). Recent studies of BIR initiated at DSBs have shown that DNA synthesis occurs by a conservative mechanism involving a migrating D-loop intermediate and is associated with a much higher rate of mutagenesis than normal S-phase synthesis. Furthermore, the invading strand is unstable and can switch to different templates increasing the risk of chromosome rearrangements. The mutagenic potential of BIR suggests it may play an important role in genome evolution as well as cancer etiology; however, it has raised the question of whether similar processes occur at collapsed replication forks.