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Mechanisms and genomic implications of break-induced replication

Nature Structural & Molecular Biology (2025)Cite this article

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Abstract

DNA double-strand breaks (DSBs) are a severe threat to genome stability, as DSB-repair mechanisms with low fidelity contribute to loss of genome integrity. Break-induced replication (BIR) is a crucial DSB-repair pathway when classical homologous recombination mechanisms fail. BIR is often triggered by stalled or collapsed replication forks, following extensive end resection that generates a single-stranded DNA substrate, which can engage either canonical homology-driven BIR, or microhomology-mediated BIR (mmBIR), which requires shorter sequence homologies than does canonical BIR. BIR is a double-edged sword: it is necessary for DSB repair, but is also culpable for introducing mutations and structural variations that are linked to cancer and genetic disorders. In this Review, we discuss BIR regulation in mammalian cells, and the role of BIR in telomere maintenance and in human disease, as well as in genome engineering. We highlight emerging findings in these areas and advances in technologies that have enabled their discovery and reshape our understanding of this enigmatic repair mechanism.

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Fig. 1: The transition from canonical replication to BIR is responsible for ALT.
Fig. 2: Consequences of break-induced replication versus microhomology-mediated break-induced replication.
Fig. 3: Break-induced replication-driven genomic amplification mechanisms.

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Acknowledgements

This work was supported by R01 CA138835, R01 CA174904 and GM 101194; a Bloom Syndrome Grant from the UPENN Orphan Disease Center; NSFGRFP grant DGE-2236662 to A.A, and an ACS-funded postdoctoral fellowship PF-23-1150186-01-DMC to H.J.

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  1. These authors contributed equally: Adel Atari, Haoyang Jiang.

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  1. Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Adel Atari, Haoyang Jiang & Roger A. Greenberg

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Atari, A., Jiang, H. & Greenberg, R.A. Mechanisms and genomic implications of break-induced replication. Nat Struct Mol Biol (2025). https://doi.org/10.1038/s41594-025-01644-z

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