Break-Induced DNA Replication

Recombination-dependent DNA replication, often called break-induced replication (BIR), was initially invoked to explain recombination events in bacteriophage but it has recently been recognized as a fundamentally important mechanism to repair double-strand chromosome breaks in eukaryotes. This mechanism appears to be critically important in the restarting of stalled and broken replication forks and in maintaining the integrity of eroded telomeres. Although BIR helps preserve genome integrity during replication, it also promotes genome instability by the production of loss of heterozygosity and the formation of nonreciprocal translocations, as well as in the generation of complex chromosomal rearrangements.The break-copy mode of recombination (as opposed to break-join), was initially proposed by Meselson and Weigle (1961). Break-copy recombination, now more commonly known as recombination-dependent DNA replication or break-induced replication (BIR), is believed to account for restarting replication at broken replication forks and may also play a central role in the maintenance of telomeres in the absence of telomerase. BIR has been studied in various model systems and has been invoked to explain chromosome rearrangements in humans. This review focuses primarily on mechanistic studies in Escherichia coli and its bacteriophages, T4 and λ, in the budding yeasts Saccharomyces cerevisiae and Kluyveromyces lactis and on apparently similar, but less well-documented, mechanisms in mammalian cells.Homology-dependent repair of DNA double-strand breaks (DSBs) occur by three major repair pathways (Pâques and Haber 1999) (Fig. 1). When both ends of the DNA share substantial homology with a donor template (a sister chromatid, a homologous chromosome, or an ectopically located segment), repair occurs almost exclusively by gene conversion (GC). If the DSB is flanked by direct repeats, then a second repair process, single-strand annealing (SSA), can occur as 5′ to 3′ resection of the DSB ends exposes complementary sequences that can anneal to each other and repair the break by the formation of a deletion. However, when only one DSB end shares homology with a donor sequence, repair occurs by BIR. There are two BIR pathways, one dependent on Rad51 recombinase and the other independent of Rad51.Open in a separate windowFigure 1.Three major repair pathways of homology-dependent recombination. Noncrossover (NCO) and crossover (CO) events are indicated. Black triangles represent resolution of Holliday junctions (HJs). Dashed lines represent new DNA synthesis. GC, gene conversion; SSA, single-strand annealing; BIR, break-induced replication.