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Gene duplication and deletion caused by over-replication at a fork barrier
Judith Oehler1, Carl A Morrow1, Matthew C Whitby2
1Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
Nature Communications
|November 25, 2023
Summary
Replication fork stalling can cause gene rearrangements. Excess DNA from merging forks may integrate elsewhere, threatening genome stability via targeted gene replacements.
Area of Science:
- Molecular Biology
- Genetics
- DNA Replication
Background:
- Replication fork stalling can lead to fork reversal, forming a four-way DNA junction.
- This process aids DNA repair and lesion bypass but risks over-replication during fork convergence.
Purpose of the Study:
- To investigate the mechanisms of gene duplication-deletion rearrangements induced by replication fork stalling.
- To determine the pathways involved in these rearrangements, distinguishing them from replication restart-associated processes.
Main Methods:
- Utilized site-specific DNA barriers in fission yeast to induce replication fork stalling.
- Analyzed gene duplication-deletion rearrangements using genetic assays.
- Assessed the requirement for specific proteins like Rad52, Rad16-Swi10, and Msh2 in the observed rearrangements.
Main Results:
- Replication fork stalling induced gene duplication-deletion rearrangements independent of replication restart and Rad51.
- These rearrangements were mechanistically similar to targeted gene replacements (TGRs).
- The process required the DNA annealing activity of Rad52, the Rad16-Swi10 nuclease, and Msh2.
Conclusions:
- Excess DNA from merging canonical and reversed replication forks can be processed by nucleases.
- This liberated DNA can integrate at ectopic sites via a TGR-like mechanism.
- Over-replication at termination sites poses a significant threat to eukaryotic genome stability.
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