2019
DOI: 10.3390/cancers11081123
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Interphase Cytogenetic Analysis of Micronucleated and Multinucleated Cells Supports the Premature Chromosome Condensation Hypothesis as the Mechanistic Origin of Chromothripsis

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 prem… Show more

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Cited by 18 publications
(19 citation statements)
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“…Another important recent development regarding the consequences of MN formation is the observation that entrapment of chromosomes in MNi may result in premature chromosome condensation of the chromosome and its fragmentation. This situation occurs when DNA replication in the MN is delayed relative to the nucleus [ 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. The resulting chromosome fragments may be incorporated into one of the daughter nuclei and undergo error-prone repair by non-homologous end joining, resulting in a massively rearranged mutant chromosome [ 52 , 53 , 57 , 58 , 59 , 60 ].…”
Section: Shattering Of Chromosomes In Mni and Their Subsequent Hypmentioning
confidence: 99%
See 1 more Smart Citation
“…Another important recent development regarding the consequences of MN formation is the observation that entrapment of chromosomes in MNi may result in premature chromosome condensation of the chromosome and its fragmentation. This situation occurs when DNA replication in the MN is delayed relative to the nucleus [ 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. The resulting chromosome fragments may be incorporated into one of the daughter nuclei and undergo error-prone repair by non-homologous end joining, resulting in a massively rearranged mutant chromosome [ 52 , 53 , 57 , 58 , 59 , 60 ].…”
Section: Shattering Of Chromosomes In Mni and Their Subsequent Hypmentioning
confidence: 99%
“…Methods to measure the pulverisation of chromosomes trapped in MNi, defective membranes in disrupted MNi, cGAS positive MNi, and leakage of DNA into the cytoplasm in cells containing MNi have been recently published [ 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ].…”
Section: Shattering Of Chromosomes In Mni and Their Subsequent Hypmentioning
confidence: 99%
“…Chromothripsis-like chromosomal rearrangement could be as well generated following particle radiation-induced localized chromosome shattering through the formation of MN in the progeny of irradiated cells [4,14,64]. Since particle radiation-induced clustered DNA lesions and chromatin decompaction at their sites are more persistent than those induced by low-LET radiation [43], they have an increased capacity to proceed to G2/M transition and undergo chromatin condensation.…”
Section: Our Model: Clustered Dna Lesions Are Transformed Through Chrmentioning
confidence: 99%
“…Therefore, full understanding of the processes underlying chromosome shattering and the formation of chromothripsis-like complex chromosomal alterations is an important step towards the clarification of the increased biological effectiveness and long-term health risk of high-LET particle irradiation. In this respect, we have recently provided experimental evidence supporting that localized chromosome shattering in micronuclei (MN) is triggered in a single catastrophic event by the dynamics of premature chromosome condensation (PCC) in asynchronous micronucleated cells [14]. Consequently, we consider it of interest to examine whether the dynamics of chromatin condensation during the cell cycle can transform persistent DNA and chromatin alterations into breaks, thereby explaining the increased efficacy of particle irradiation for killing cancerous cells and the formation of chromothripsis-like chromosomal alterations.…”
Section: Introductionmentioning
confidence: 99%
“…The CBMN assay quantifies the frequency of micronuclei (MN) in binucleated cells (BNCs) derived from peripheral lymphocytes. Whole chromosomes, as well as chromosome fragments, can be in micronuclei that lag behind at anaphase during nuclear division; which can persist up to 1 year and may contribute to genomic instability through chromosome shattering within MN caused by premature chromosome condensation in case of asynchronous cellcycle progression between main nuclei and MN [3,4]. The CBMN is a particularly useful biodosimetric tool for quantifying radiation-induced chromosomal damage for population triage due to the simplicity of MN scoring and the availability of high-throughput fully automated systems [5][6][7][8][9].…”
Section: Introductionmentioning
confidence: 99%