Abstract
DNA double-strand break (DSB) repair is critical for cell survival. A diverse range of organisms from bacteria to humans rely on homologous recombination for accurate DSB repair. This requires both coordinate action of the two ends of a DSB and stringent control of the resultant DNA replication to prevent unwarranted DNA amplification and aneuploidy. In Escherichia coli, RecBCD enzyme is responsible for the initial steps of homologous recombination. Previous work has revealed recD mutants to be nuclease defective but recombination proficient. Despite this proficiency, we show here that a recD null mutant is defective for the repair of a two-ended DSB and that this defect is associated with unregulated chromosome amplification and defective chromosome segregation. Our results demonstrate that RecBCD plays an important role in avoiding this amplification by coordinating the two recombining ends in a manner that prevents divergent replication forks progressing away from the DSB site.
Highlights
Organisms as distantly related as humans and bacteria have evolved sophisticated mechanisms to ensure the stable inheritance of their genomes through successive generations
Genome instability per se need not be detrimental as aneuploidy is found in human hepatocytes [5], aneuploidy and copy number variations are found in neurons [6], and mosaic aneuploidy contributes to adaptability in organisms such as Leishmania [7]
We show that cells lacking RecD are unable to coordinate the two ends of the double-strand break (DSB) and this results in aberrant DNA replication and defective chromosome segregation
Summary
Organisms as distantly related as humans and bacteria have evolved sophisticated mechanisms to ensure the stable inheritance of their genomes through successive generations. Genome instability is an enabling characteristic of cancer [1] and a direct cause of several human syndromes (e.g. Down syndrome and Klinefelter syndrome). These have been attributed to aberrant DNA replication Since recombination involves DNA synthesis and can lead to chromosomal amplification and duplication via recombinationdependent replication in prokaryotes and break-induced replication in eukaryotes [8,9,10,11], it is interesting to consider how segregation errors resulting in aneuploidy and copy number variation may arise from improper interactions between recombination and DNA replication
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