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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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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. |
format | Online Article Text |
id | pubmed-10307639 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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