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Updated: Apr 28, 2026
Author Spotlight: Characterizing DNA Replication of Pathogenic Repeats to Uncover Mechanisms of Replication Fork Stalling and Expansion
Published on: September 13, 2024
Break-induced replication is a source of mutation clusters underlying kataegis
Cynthia J Sakofsky1, Steven A Roberts2, Ewa Malc3
1Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242-1324, USA; Department of Biology, School of Science, IUPUI, Indianapolis, IN 46202-5132, USA.
Abstract:
Clusters of simultaneous multiple mutations can be a source of rapid change during carcinogenesis and evolution. Such mutation clusters have been recently shown to originate from DNA damage within long single-stranded DNA (ssDNA) formed at resected double-strand breaks and dysfunctional replication forks. Here, we identify double-strand break (DSB)-induced replication (BIR) as another powerful source of mutation clusters that formed in nearly half of wild-type yeast cells undergoing BIR in the presence of alkylating damage. Clustered mutations were primarily formed along the track of DNA synthesis and were frequently associated with additional breakage and rearrangements. Moreover, the base specificity, strand coordination, and strand bias of the mutation spectrum were consistent with mutations arising from damage in persistent ssDNA stretches within unconventional replication intermediates. Altogether, these features closely resemble kataegic events in cancers, suggesting that replication intermediates during BIR may be the most prominent source of mutation clusters across species.
Insights
Double-strand break-induced replication (BIR) creates mutation clusters in yeast, similar to cancer kataegis. These clusters arise from DNA damage in single-stranded DNA during BIR replication intermediates.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Mutation clusters drive rapid evolutionary and carcinogenic changes.
- Previous studies linked mutation clusters to DNA damage in single-stranded DNA (ssDNA) at resected double-strand breaks and stalled replication forks.
Purpose of the Study:
- To investigate double-strand break (DSB)-induced break-induced replication (BIR) as a novel source of mutation clusters.
- To characterize the nature and mechanisms of mutation clusters formed during BIR.
Main Methods:
- Induction of BIR in wild-type yeast cells with alkylating damage.
- Analysis of mutation patterns, including base specificity, strand coordination, and bias.
- Characterization of associated DNA breakage and rearrangements.
Main Results:
- BIR generated mutation clusters in nearly half of yeast cells.
- Mutations were concentrated along the DNA synthesis track.
- BIR-associated mutation clusters showed features consistent with damage in persistent ssDNA within unconventional replication intermediates.
- These clusters were linked to additional breakage and rearrangements.
Conclusions:
- DSB-induced BIR is a significant source of mutation clusters.
- The findings suggest BIR replication intermediates are a major source of mutation clusters across species.
- This mechanism may contribute to kataegis-like events observed in cancer genomes.
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