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Mitotic clustering of pulverized chromosomes from micronuclei

View ORCID ProfileYu-Fen Lin, View ORCID ProfileJose Espejo Valle-Inclan, View ORCID ProfileAlice Mazzagatti, View ORCID ProfileQing Hu, View ORCID ProfileElizabeth G. Maurais, Alison Guyer, View ORCID ProfileJacob T. Sanders, View ORCID ProfileJustin Engel, View ORCID ProfileGiaochau Nguyen, View ORCID ProfileDaniel Bronder, View ORCID ProfileSamuel F. Bakhoum, View ORCID ProfileIsidro Cortés-Ciriano, View ORCID ProfilePeter Ly
doi: https://doi.org/10.1101/2022.07.19.500697
Yu-Fen Lin
1Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
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Jose Espejo Valle-Inclan
2European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, United Kingdom
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Alice Mazzagatti
1Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
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Qing Hu
1Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
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Elizabeth G. Maurais
1Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
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Alison Guyer
1Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
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Jacob T. Sanders
1Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
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Justin Engel
1Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
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Giaochau Nguyen
1Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
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Daniel Bronder
3Human Oncology and Pathogenesis Program, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, United States
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Samuel F. Bakhoum
3Human Oncology and Pathogenesis Program, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, United States
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Isidro Cortés-Ciriano
2European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, United Kingdom
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  • For correspondence: peter.ly@utsouthwestern.edu icortes@ebi.ac.uk
Peter Ly
1Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
4Department of Cell Biology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States
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  • For correspondence: peter.ly@utsouthwestern.edu icortes@ebi.ac.uk
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Abstract

Complex genome rearrangements can be generated by the catastrophic shattering of mis-segregated chromosomes trapped within micronuclei through a process known as chromothripsis. Since each chromosome harbors a single centromere, how acentric fragments derived from shattered chromosomes are inherited between daughter cells during mitosis remains unknown. Here we tracked micronucleated chromosomes by live-cell imaging and show that acentric fragments cluster in close spatial proximity throughout mitosis for biased partitioning to a single daughter cell. Mechanistically, the CIP2A-TOPB1 complex prematurely associates with DNA lesions within ruptured micronuclei during interphase, which poises chromosome fragments for clustering upon mitotic entry. Inactivation of CIP2A or TOPBP1 caused pulverized chromosomes to untether and disperse throughout the mitotic cell, consequently resulting in the mis-accumulation of DNA fragments in the cytoplasm. The inheritance of shattered chromosomes by a single daughter cell suggests that micronucleation can drive complex rearrangements that lack the DNA copy number oscillations characteristic of canonical chromothripsis. Comprehensive analysis of pan-cancer whole-genome sequencing data revealed clusters of DNA copy number-neutral rearrangements – termed balanced chromothripsis – across diverse cancer types resulting in the acquisition of known driver events. Thus, distinct patterns of chromothripsis can be explained by the spatial mitotic clustering of pulverized chromosomes from micronuclei.

Competing Interest Statement

S.F.B. owns equity in, receives compensation from, and serves as a consultant and the Scientific Advisory Board and Board of Directors of Volastra Therapeutics, Inc. All other authors do not have any competing interests to declare.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 20, 2022.
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Mitotic clustering of pulverized chromosomes from micronuclei
Yu-Fen Lin, Jose Espejo Valle-Inclan, Alice Mazzagatti, Qing Hu, Elizabeth G. Maurais, Alison Guyer, Jacob T. Sanders, Justin Engel, Giaochau Nguyen, Daniel Bronder, Samuel F. Bakhoum, Isidro Cortés-Ciriano, Peter Ly
bioRxiv 2022.07.19.500697; doi: https://doi.org/10.1101/2022.07.19.500697
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Mitotic clustering of pulverized chromosomes from micronuclei
Yu-Fen Lin, Jose Espejo Valle-Inclan, Alice Mazzagatti, Qing Hu, Elizabeth G. Maurais, Alison Guyer, Jacob T. Sanders, Justin Engel, Giaochau Nguyen, Daniel Bronder, Samuel F. Bakhoum, Isidro Cortés-Ciriano, Peter Ly
bioRxiv 2022.07.19.500697; doi: https://doi.org/10.1101/2022.07.19.500697

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