title: Break-induced replication repair of damaged forks induces genomic duplications in human cells.
abstract: In budding yeast, one-ended DNA double-strand breaks (DSBs) and damaged replication forks are repaired by break-induced replication (BIR), a homologous recombination pathway that requires the Pol32 subunit of DNA polymerase delta. DNA replication stress is prevalent in cancer, but BIR has not been characterized in mammals. In a cyclin E overexpression model of DNA replication stress, POLD3, the human ortholog of POL32, was required for cell cycle progression and processive DNA synthesis. Segmental genomic duplications induced by cyclin E overexpression were also dependent on POLD3, as were BIR-mediated recombination events captured with a specialized DSB repair assay. We propose that BIR repairs damaged replication forks in mammals, accounting for the high frequency of genomic duplications in human cancers.
authors: Department of Molecular Biology, University of Geneva, 1205 Geneva, Switzerland.
authors: Lorenzo
authors: L
authors: Costantino
authors: Sotirios K
authors: SK
authors: Sotiriou
authors: Juha K
authors: JK
authors: Rantala
authors: Simon
authors: S
authors: Magin
authors: Emil
authors: E
authors: Mladenov
authors: Thomas
authors: T
authors: Helleday
authors: James E
authors: JE
authors: Haber
authors: George
authors: G
authors: Iliakis
authors: Olli P
authors: OP
authors: Kallioniemi
authors: Thanos D
authors: TD
authors: Halazonetis
mesh_terms: D002453:Cell Cycle; D019927:Cyclin E / Q000096:biosynthesis / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004258:DNA Polymerase III / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D020440:Gene Duplication; D006801:Humans; D009369:Neoplasms / Q000235:genetics*
chemical_list: D019927:Cyclin E; C435720:POLD3 protein, human; D004258:DNA Polymerase III