Gene duplication and deletion caused by over-replication at a fork barrier

Judith Oehler, Carl A. Morrow and Matthew C. Whitby ()
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Judith Oehler: University of Oxford
Carl A. Morrow: University of Oxford
Matthew C. Whitby: University of Oxford

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Replication fork stalling can provoke fork reversal to form a four-way DNA junction. This remodelling of the replication fork can facilitate repair, aid bypass of DNA lesions, and enable replication restart, but may also pose a risk of over-replication during fork convergence. We show that replication fork stalling at a site-specific barrier in fission yeast can induce gene duplication-deletion rearrangements that are independent of replication restart-associated template switching and Rad51-dependent multi-invasion. Instead, they resemble targeted gene replacements (TGRs), requiring the DNA annealing activity of Rad52, the 3’-flap nuclease Rad16-Swi10, and mismatch repair protein Msh2. We propose that excess DNA, generated during the merging of a canonical fork with a reversed fork, can be liberated by a nuclease and integrated at an ectopic site via a TGR-like mechanism. This highlights how over-replication at replication termination sites can threaten genome stability in eukaryotes.

Date: 2023
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DOI: 10.1038/s41467-023-43494-7

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