Break-Induced Replication Dynamics in Eukaryotic Genomes

Break-induced replication (BIR) is a specialised repair pathway activated when only one end of a DNA double-strand break (DSB) can locate homologous sequences elsewhere in the genome. Unlike canonical replication from defined origins, BIR initiates from a single invading end, assembles a migrating replication bubble, and can copy hundreds of kilobases of DNA. This mode of repair is inherently error-prone: extended single-stranded DNA (ssDNA) accumulates behind the bubble, exposing regions to damage and facilitating template switching. Key enzymatic players include the Rad51 recombinase, which catalyses strand invasion; the Polδ holoenzyme, which drives new DNA synthesis; and single-stranded DNA-binding proteins such as RPA, which stabilise resected ends. BIR is regulated by DNA resection factors, checkpoint kinases and helicases that together determine fork stability and choice of repair subpathway. Although essential for recovery from collapsed replication forks and eroded telomeres, BIR can generate mutations, structural variations and copy-number changes that contribute to evolution, development and disease, notably in oncogenic contexts. Recent work has begun to unravel specialised subpathways of BIR, the mechanisms underlying error accumulation and the interplay with other repair outcomes such as nonhomologous end joining and de novo telomere addition.

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Break-Induced Replication Dynamics in Eukaryotic Genomes publication trend

The graph below shows the total number of articles in break-induced replication dynamics in eukaryotic genomes across all publications each year (not limited to Nature Index journals).

Technical terms

Double-strand break (DSB): A lesion in which both strands of the DNA helix are severed, necessitating specialised repair pathways.

Break-induced replication (BIR): A homology-driven DNA repair mechanism initiated from a single broken end that recreates a replication fork-like structure capable of extensive DNA synthesis.

Microhomology-mediated template switching: A process whereby very short homologous sequences (typically 2–10 bp) at DNA ends guide aberrant annealing and strand exchange, leading to insertions or rearrangements.

Replication protein A (RPA): A heterotrimeric complex that binds and stabilises ssDNA during DNA replication and repair, preventing secondary structure formation and nucleolytic degradation.

Multi-invasion-induced rearrangement (MIR): A pathway in which multiple strand invasions during homologous recombination produce complex structural variants through successive repair events.

Hypermutagenesis: A markedly elevated local mutation rate that often accompanies BIR intermediates, driven by ssDNA exposure and error-prone polymerase activity.

References

1. Break-Induced Replication Is Highly Inaccurate. PLOS Biology (2011).
2. RPA and Rad27 limit templated and inverted insertions at DNA breaks. Nucleic Acids Research (2024).
3. Delineation of two multi-invasion-induced rearrangement pathways that differently affect genome stability. Genes & Development (2023).
4. Break-Induced Replication Is a Source of Mutation Clusters Underlying Kataegis. Cell Reports (2014).
5. Repair of base damage within break-induced replication intermediates promotes kataegis associated with chromosome rearrangements. Nucleic Acids Research (2019).