DNA Synthesis Generates Terminal Duplications That Seal End-to-End Chromosome Fusions

Abstract

End-to-end chromosome fusions that occur in the context of telomerase deficiency can trigger genomic duplications. For over 70 years these duplications have been attributed solely to Breakage-Fusion-Bridge cycles. To test this hypothesis, we examined end-to-end fusions isolated from C. elegans telomere replication mutants. Genome level rearrangements revealed fused chromosome ends possessing interrupted terminal duplications accompanied by template switching events. These features are very similar to disease-associated duplications of interstitial segments of the human genome. A model termed Fork Stalling and Template Switching has been proposed previously to explain such duplications, where promiscuous replication of large, non-contiguous segments of the genome occurs. Thus, a DNA synthesis-based process may create duplications that seal end-to-end fusions, in the absence of Breakage-Fusion-Bridge cycles

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