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Open AccessArticle

Interphase Cytogenetic Analysis of Micronucleated and Multinucleated Cells Supports the Premature Chromosome Condensation Hypothesis as the Mechanistic Origin of Chromothripsis

1
Laboratory of Health Physics, Radiobiology & Cytogenetics, Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, National Centre for Scientific Research “Demokritos”, 15341 Agia Paraskevi, Greece
2
DNA Damage Laboratory, Physics Department, School of Mathematical and Physical Sciences, National Technical University of Athens (NTUA), 15780 Zografou, Greece
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(8), 1123; https://doi.org/10.3390/cancers11081123
Received: 31 May 2019 / Revised: 26 July 2019 / Accepted: 3 August 2019 / Published: 6 August 2019
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Abstract

The discovery of chromothripsis in cancer genomes challenges the long-standing concept of carcinogenesis as the result of progressive genetic events. Despite recent advances in describing chromothripsis, its mechanistic origin remains elusive. The prevailing conception is that it arises from a massive accumulation of fragmented DNA inside micronuclei (MN), whose defective nuclear envelope ruptures or leads to aberrant DNA replication, before main nuclei enter mitosis. An alternative hypothesis is that the premature chromosome condensation (PCC) dynamics in asynchronous micronucleated cells underlie chromosome shattering in a single catastrophic event, a hallmark of chromothripsis. Specifically, when main nuclei enter mitosis, premature chromatin condensation provokes the shattering of chromosomes entrapped inside MN, if they are still undergoing DNA replication. To test this hypothesis, the agent RO-3306, a selective ATP-competitive inhibitor of CDK1 that promotes cell cycle arrest at the G2/M boundary, was used in this study to control the degree of cell cycle asynchrony between main nuclei and MN. By delaying the entrance of main nuclei into mitosis, additional time was allowed for the completion of DNA replication and duplication of chromosomes inside MN. We performed interphase cytogenetic analysis using asynchronous micronucleated cells generated by exposure of human lymphocytes to γ-rays, and heterophasic multinucleated Chinese hamster ovary (CHO) cells generated by cell fusion procedures. Our results demonstrate that the PCC dynamics during asynchronous mitosis in micronucleated or multinucleated cells are an important determinant of chromosome shattering and may underlie the mechanistic origin of chromothripsis. View Full-Text
Keywords: premature chromosome condensation (PCC); micronuclei; chromothripsis; chromosome shattering; chromosomal instability; RO-3306; PCC hypothesis; PCC dynamics premature chromosome condensation (PCC); micronuclei; chromothripsis; chromosome shattering; chromosomal instability; RO-3306; PCC hypothesis; PCC dynamics
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Pantelias, A.; Karachristou, I.; Georgakilas, A.G.; Terzoudi, G.I. Interphase Cytogenetic Analysis of Micronucleated and Multinucleated Cells Supports the Premature Chromosome Condensation Hypothesis as the Mechanistic Origin of Chromothripsis. Cancers 2019, 11, 1123.

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