title: Ultrafine anaphase bridges, broken DNA and illegitimate recombination induced by a replication fork barrier.
abstract: Most DNA double-strand breaks (DSBs) in S- and G2-phase cells are repaired accurately by Rad51-dependent sister chromatid recombination. However, a minority give rise to gross chromosome rearrangements (GCRs), which can result in disease/death. What determines whether a DSB is repaired accurately or inaccurately is currently unclear. We provide evidence that suggests that perturbing replication by a non-programmed protein-DNA replication fork barrier results in the persistence of replication intermediates (most likely regions of unreplicated DNA) into mitosis, which results in anaphase bridge formation and ultimately to DNA breakage. However, unlike previously characterised replication-associated DSBs, these breaks are repaired mainly by Rad51-independent processes such as single-strand annealing, and are therefore prone to generate GCRs. These data highlight how a replication-associated DSB can be predisposed to give rise to genome rearrangements in eukaryotes.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
authors.forename: Sevil
authors.initials: S
authors.lastname: Sofueva
authors.forename: Fekret
authors.initials: F
authors.lastname: Osman
authors.forename: Alexander
authors.initials: A
authors.lastname: Lorenz
authors.forename: Roland
authors.initials: R
authors.lastname: Steinacher
authors.forename: Stefania
authors.initials: S
authors.lastname: Castagnetti
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ledesma
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Whitby
mesh_terms: D000705:Anaphase / Q000235:genetics; D002872:Chromosome Deletion; D004247:DNA / Q000648:ultrastructure; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000378:metabolism; D004261:DNA Replication; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism; D056968:Lac Repressors / Q000378:metabolism; D008938:Mitosis; D009154:Mutation; D009875:Operator Regions, Genetic; D011995:Recombination, Genetic; D012568:Schizosaccharomyces / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism
chemical_list: D019309:Epstein-Barr Virus Nuclear Antigens; D056968:Lac Repressors; D029702:Schizosaccharomyces pombe Proteins; D004247:DNA; D004265:DNA Helicases; C468287:Pfh1 protein, S pombe; C417029:EBV-encoded nuclear antigen 1