Abstract
Problems that arise during DNA replication can drive genomic alterations that are instrumental in the development of cancers and many human genetic disorders. Replication fork barriers are a commonly encountered problem, which can cause fork collapse and act as hotspots for replication termination. Collapsed forks can be rescued by homologous recombination, which restarts replication. However, replication restart is relatively slow and, therefore, replication termination may frequently occur by an active fork converging on a collapsed fork. We find that this type of non-canonical fork convergence in fission yeast is prone to trigger deletions between repetitive DNA sequences via a mechanism we call Inter-Fork Strand Annealing (IFSA) that depends on the recombination proteins Rad52, Exo1 and Mus81, and is countered by the FANCM-related DNA helicase Fml1. Based on our findings, we propose that IFSA is a potential threat to genomic stability in eukaryotes.
Highlights
Eukaryotic DNA replication initiates at multiple origin sites along each chromosome and terminates when replication forks (RFs) from adjacent origins converge
We have shown that non-canonical RF convergence, involving a regular fork converging on a collapsed fork, can promote recombination between DNA repeats that flank the site of replication termination by a process we call Inter-Fork Strand Annealing (IFSA), which involves Rad52-mediated strand annealing between the two RFs
We, and others, have reported that recombination-dependent replication (RDR), promoted by fork collapse at the RTS1 barrier, generates chromosomal rearrangements and copynumber variations (CNVs), both during the act of restarting replication, and from the increase in template switching associated with the restarted fork (Ahn et al, 2005; Lambert et al, 2010, 2005; Mizuno et al, 2009, 2013; Nguyen et al, 2015)
Summary
Eukaryotic DNA replication initiates at multiple origin sites along each chromosome and terminates when replication forks (RFs) from adjacent origins converge. To guard against the possibility that this second RF may fail, cells deploy homologous recombination (HR) enzymes to the collapsed fork, which can restart replication (Lambert et al, 2010; Mohebi et al, 2015; Nguyen et al, 2015; Yeeles et al, 2013). This so-called recombination-dependent replication (RDR) helps ensure that DNA is fully replicated prior to sister chromatid segregation, thereby avoiding mitotic catastrophes
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