Mitotic clustering of pulverized chromosomes from micronuclei Journal Article
| Authors: | Lin, Y. F.; Hu, Q.; Mazzagatti, A.; Valle-Inclán, J. E.; Maurais, E. G.; Dahiya, R.; Guyer, A.; Sanders, J. T.; Engel, J. L.; Nguyen, G.; Bronder, D.; Bakhoum, S. F.; Cortés-Ciriano, I.; Ly, P. |
| Article Title: | Mitotic clustering of pulverized chromosomes from micronuclei |
| 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. © 2023, The Author(s). |
| Keywords: | osteosarcoma; controlled study; unclassified drug; human cell; genetics; neoplasm; neoplasms; mitosis; chromosome; metabolism; dna damage; melanoma; protein protein interaction; daughter cell; tumor suppressor gene; dna; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; gene fusion; fusion gene; chromosome rearrangement; genome; prostate adenocarcinoma; cell nucleus; gene dosage; tumor; breast adenocarcinoma; topbp1 protein; transcription factor fkhrl1; chromosomes; liposarcoma; centromere; phosphoprotein phosphatase; cell; pten gene; scaffold protein; interphase; micronucleus; inheritance; chromothripsis; cancer; humans; human; article; live cell imaging; foxo3 gene; extrachromosomal dna; tmprss2 erg gene; transitional cell carcinoma of the bladder; cip2a protein; arid2 gene; ccdc170 esr1 gene; cct5 fam173b gene; rab3c pde4d gene; soft tissue liposarcoma |
| Journal Title: | Nature |
| Volume: | 618 |
| Issue: | 7967 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-06-29 |
| Start Page: | 1041 |
| End Page: | 1048 |
| Language: | English |
| DOI: | 10.1038/s41586-023-05974-0 |
| PUBMED: | 37165191 |
| PROVIDER: | scopus |
| PMCID: | PMC10307639 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work