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Mitotic clustering of pulverized chromosomes from micronuclei

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 c...

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Autores principales: Lin, Yu-Fen, Hu, Qing, Mazzagatti, Alice, Valle-Inclán, Jose Espejo, Maurais, Elizabeth G., Dahiya, Rashmi, Guyer, Alison, Sanders, Jacob T., Engel, Justin L., Nguyen, Giaochau, Bronder, Daniel, Bakhoum, Samuel F., Cortés-Ciriano, Isidro, Ly, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10307639/
https://www.ncbi.nlm.nih.gov/pubmed/37165191
http://dx.doi.org/10.1038/s41586-023-05974-0
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author Lin, Yu-Fen
Hu, Qing
Mazzagatti, Alice
Valle-Inclán, Jose Espejo
Maurais, Elizabeth G.
Dahiya, Rashmi
Guyer, Alison
Sanders, Jacob T.
Engel, Justin L.
Nguyen, Giaochau
Bronder, Daniel
Bakhoum, Samuel F.
Cortés-Ciriano, Isidro
Ly, Peter
author_facet Lin, Yu-Fen
Hu, Qing
Mazzagatti, Alice
Valle-Inclán, Jose Espejo
Maurais, Elizabeth G.
Dahiya, Rashmi
Guyer, Alison
Sanders, Jacob T.
Engel, Justin L.
Nguyen, Giaochau
Bronder, Daniel
Bakhoum, Samuel F.
Cortés-Ciriano, Isidro
Ly, Peter
author_sort Lin, Yu-Fen
collection PubMed
description 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.
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spelling pubmed-103076392023-06-30 Mitotic clustering of pulverized chromosomes from micronuclei Lin, Yu-Fen Hu, Qing Mazzagatti, Alice Valle-Inclán, Jose Espejo Maurais, Elizabeth G. Dahiya, Rashmi Guyer, Alison Sanders, Jacob T. Engel, Justin L. Nguyen, Giaochau Bronder, Daniel Bakhoum, Samuel F. Cortés-Ciriano, Isidro Ly, Peter Nature Article 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. Nature Publishing Group UK 2023-05-10 2023 /pmc/articles/PMC10307639/ /pubmed/37165191 http://dx.doi.org/10.1038/s41586-023-05974-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Lin, Yu-Fen
Hu, Qing
Mazzagatti, Alice
Valle-Inclán, Jose Espejo
Maurais, Elizabeth G.
Dahiya, Rashmi
Guyer, Alison
Sanders, Jacob T.
Engel, Justin L.
Nguyen, Giaochau
Bronder, Daniel
Bakhoum, Samuel F.
Cortés-Ciriano, Isidro
Ly, Peter
Mitotic clustering of pulverized chromosomes from micronuclei
title Mitotic clustering of pulverized chromosomes from micronuclei
title_full Mitotic clustering of pulverized chromosomes from micronuclei
title_fullStr Mitotic clustering of pulverized chromosomes from micronuclei
title_full_unstemmed Mitotic clustering of pulverized chromosomes from micronuclei
title_short Mitotic clustering of pulverized chromosomes from micronuclei
title_sort mitotic clustering of pulverized chromosomes from micronuclei
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10307639/
https://www.ncbi.nlm.nih.gov/pubmed/37165191
http://dx.doi.org/10.1038/s41586-023-05974-0
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