title: Chromothripsis and Kataegis Induced by Telomere Crisis.
abstract: Telomere crisis occurs during tumorigenesis when depletion of the telomere reserve leads to frequent telomere fusions. The resulting dicentric chromosomes have been proposed to drive genome instability. Here, we examine the fate of dicentric human chromosomes in telomere crisis. We observed that dicentric chromosomes invariably persisted through mitosis and developed into 50-200 μm chromatin bridges connecting the daughter cells. Before their resolution at 3-20 hr after anaphase, the chromatin bridges induced nuclear envelope rupture in interphase, accumulated the cytoplasmic 3' nuclease TREX1, and developed RPA-coated single stranded (ss) DNA. CRISPR knockouts showed that TREX1 contributed to the generation of the ssDNA and the resolution of the chromatin bridges. Post-crisis clones showed chromothripsis and kataegis, presumably resulting from DNA repair and APOBEC editing of the fragmented chromatin bridge DNA. We propose that chromothripsis in human cancer may arise through TREX1-mediated fragmentation of dicentric chromosomes formed in telomere crisis.
authors.affiliation: Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: John
authors.initials: J
authors.lastname: Maciejowski
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton Cambridge, CB10 1SA, UK.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Nazario
authors.initials: N
authors.lastname: Bosco
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton Cambridge, CB10 1SA, UK. Electronic address: pc8@sanger.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address: delange@mail.rockefeller.edu.
authors.forename: Titia
authors.initials: T
authors.lastname: de Lange
mesh_terms: D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D002877:Chromosomes, Human; D048749:Cytokinesis; D004277:DNA, Single-Stranded / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D008938:Mitosis; D009369:Neoplasms / Q000235:genetics*; D009685:Nuclear Envelope / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D016615:Telomere
chemical_list: D004277:DNA, Single-Stranded; D010750:Phosphoproteins; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1
keywords: APOBEC; NERDI; TREX1; chromothripsis; dicentric chromosome; kataegis; telomere crisis