title: Generation of Gross Chromosomal Rearrangements by a Single Engineered DNA Double Strand Break.
abstract: Gross chromosomal rearrangements (GCRs), including translocations, inversions amplifications, and deletions, can be causal events leading to malignant transformation. GCRs are thought to be triggered by DNA double strand breaks (DSBs), which in turn can be spontaneous or induced by external agents (eg. cytotoxic chemotherapy, ionizing radiation). It has been shown that induction of DNA DSBs at two defined loci can produce stable balanced chromosomal translocations, however, a single engineered DNA DSB could not. Herein, we report that although a single engineered DNA DSB in H2AX "knockdown" cells did not generate GCRs, repair of a single engineered DNA DSB in fibroblasts that had ablated H2ax did produce clonal, stable GCRs, including balanced translocations and megabase-pair inversions. Upon correction of the H2ax deficiency, cells no longer generated GCRs following a single engineered DNA DSB. These findings demonstrate that clonal, stable GCRs can be produced by a single engineered DNA DSB in H2ax knockout cells, and that the production of these GCRs is ameliorated by H2ax expression.
authors.affiliation: Genetics Branch National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: Genetics Branch National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Genetics Branch National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Roschke
authors.affiliation: Genetics Branch National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tamas
authors.initials: T
authors.lastname: Varga
authors.affiliation: Genetics Branch National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Aplan
mesh_terms: D002460:Cell Line; D002875:Chromosomes; D053903:DNA Breaks, Double-Stranded; D005347:Fibroblasts; D015321:Gene Rearrangement; D006657:Histones / Q000172:deficiency; D006801:Humans
chemical_list: C468783:H2AX protein, human; D006657:Histones