학술논문
Mitotic clustering of pulverized chromosomes from micronuclei.
Document Type
Academic Journal
Author
Lin YF; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Hu Q; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Mazzagatti A; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Valle-Inclán JE; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK.; Maurais EG; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Dahiya R; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Guyer A; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Interdisciplinary Biomedical Graduate Program, University of Pittsburgh, Pittsburgh, PA, USA.; Sanders JT; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, TN, USA.; Engel JL; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Nguyen G; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Bronder D; Human Oncology and Pathogenesis Program, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Bakhoum SF; Human Oncology and Pathogenesis Program, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Cortés-Ciriano I; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK. icortes@ebi.ac.uk.; Ly P; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. peter.ly@utsouthwestern.edu.; Department of Cell Biology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. peter.ly@utsouthwestern.edu.
Source
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
Subject
Language
English
Abstract
Complex genome rearrangements can be generated by the catastrophic pulverization of missegregated chromosomes trapped within micronuclei through a process known as chromothripsis 1-5 . As each chromosome contains a single centromere, it remains unclear how acentric fragments derived from shattered chromosomes are inherited between daughter cells during mitosis 6 . Here we tracked micronucleated chromosomes with live-cell imaging and show that acentric fragments cluster in close spatial proximity throughout mitosis for asymmetric inheritance by a single daughter cell. Mechanistically, the CIP2A-TOPBP1 complex prematurely associates with DNA lesions within ruptured micronuclei during interphase, which poises pulverized chromosomes for clustering upon mitotic entry. Inactivation of CIP2A-TOPBP1 caused acentric fragments to disperse throughout the mitotic cytoplasm, stochastically partition into the nucleus of both daughter cells and aberrantly misaccumulate as cytoplasmic DNA. Mitotic clustering facilitates the reassembly of acentric fragments into rearranged chromosomes lacking the extensive DNA copy-number losses that are characteristic of canonical chromothripsis. Comprehensive analysis of pan-cancer genomes revealed clusters of DNA copy-number-neutral rearrangements-termed balanced chromothripsis-across diverse tumour types resulting in the acquisition of known cancer driver events. Thus, distinct patterns of chromothripsis can be explained by the spatial clustering of pulverized chromosomes from micronuclei.
(© 2023. The Author(s).)
(© 2023. The Author(s).)