Mitotic clustering of pulverized chromosomes from micronuclei

Yu-Fen Lin, Qing Hu, Alice Mazzagatti, Jose Espejo Valle-Inclán, Elizabeth G. Maurais, Rashmi Dahiya, Alison Guyer, Jacob T. Sanders, Justin L. Engel, Giaochau Nguyen, Daniel Bronder, Samuel F. Bakhoum, Isidro Cortés-Ciriano () and Peter Ly ()
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Yu-Fen Lin: University of Texas Southwestern Medical Center
Qing Hu: University of Texas Southwestern Medical Center
Alice Mazzagatti: University of Texas Southwestern Medical Center
Jose Espejo Valle-Inclán: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
Elizabeth G. Maurais: University of Texas Southwestern Medical Center
Rashmi Dahiya: University of Texas Southwestern Medical Center
Alison Guyer: University of Texas Southwestern Medical Center
Jacob T. Sanders: University of Texas Southwestern Medical Center
Justin L. Engel: University of Texas Southwestern Medical Center
Giaochau Nguyen: University of Texas Southwestern Medical Center
Daniel Bronder: Memorial Sloan Kettering Cancer Center
Samuel F. Bakhoum: Memorial Sloan Kettering Cancer Center
Isidro Cortés-Ciriano: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
Peter Ly: University of Texas Southwestern Medical Center

Nature, 2023, vol. 618, issue 7967, 1041-1048

Abstract: Abstract Complex genome rearrangements can be generated by the catastrophic pulverization of missegregated chromosomes trapped within micronuclei through a process known as chromothripsis1–5. As each chromosome contains a single centromere, it remains unclear how acentric fragments derived from shattered chromosomes are inherited between daughter cells during mitosis6. 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.

Date: 2023
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DOI: 10.1038/s41586-023-05974-0

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