title: Chromothripsis from DNA damage in micronuclei.
abstract: Genome sequencing has uncovered a new mutational phenomenon in cancer and congenital disorders called chromothripsis. Chromothripsis is characterized by extensive genomic rearrangements and an oscillating pattern of DNA copy number levels, all curiously restricted to one or a few chromosomes. The mechanism for chromothripsis is unknown, but we previously proposed that it could occur through the physical isolation of chromosomes in aberrant nuclear structures called micronuclei. Here, using a combination of live cell imaging and single-cell genome sequencing, we demonstrate that micronucleus formation can indeed generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. These events are restricted to the mis-segregated chromosome and occur within one cell division. We demonstrate that the mechanism for chromothripsis can involve the fragmentation and subsequent reassembly of a single chromatid from a micronucleus. Collectively, these experiments establish a new mutational process of which chromothripsis is one extreme outcome.
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [3] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA [4] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Cheng-Zhong
authors.initials: CZ
authors.lastname: Zhang
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Spektor
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Hauke
authors.initials: H
authors.lastname: Cornils
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Francis
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Jackson
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Shiwei
authors.initials: S
authors.lastname: Liu
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA [3] Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA [4] Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA [3] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [4] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
authors.forename: David
authors.initials: D
authors.lastname: Pellman
mesh_terms: D002460:Cell Line; D002470:Cell Survival; D019457:Chromosome Breakage; D020090:Chromosome Segregation / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D004249:DNA Damage; D015321:Gene Rearrangement / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D048629:Micronuclei, Chromosome-Defective; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics; D016196:S Phase / Q000235:genetics; D059010:Single-Cell Analysis