Stress induced by premature chromatin condensation triggers chromosome shattering and chromothripsis at DNA sites still replicating in micronuclei or multinucleate cells when primary nuclei enter mitosis

Terzoudi, Georgia I.; Karakosta, Maria; Pantelias, Antonio; Hatzi, Vasiliki I.; Karachristou, Ioanna; Pantelias, Gabriel E.

doi:10.1016/j.mrgentox.2015.07.014

Cited by 36 publications

(29 citation statements)

References 28 publications

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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%

“…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%

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Cytokinesis-Block Micronucleus Cytome Assay Evolution into a More Comprehensive Method to Measure Chromosomal Instability

Fenech

2020

Genes

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This review describes the cytokinesis-block micronucleus (CBMN) cytome assay and its evolution into a molecular cytogenetic method of chromosomal instability (CIN). Micronuclei (MNi) originate from whole chromosomes or chromosome fragments that fail to segregate to the poles of the cell during mitosis. These lagging chromosomes are excluded from the daughter nuclei and are enveloped in their own membrane to form MNi. The CBMN assay was developed to allow MNi to be scored exclusively in once-divided binucleated cells, which enables accurate measurement of chromosome breakage or loss without confounding by non-dividing cells that cannot express MNi. The CBMN assay can be applied to cell lines in vitro and cells such as lymphocytes that can be stimulated to divide ex vivo. In the CBMN assay, other CIN biomarkers such as nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) are also measured. Use of centromere, telomere, and chromosome painting probes provides further insights into the mechanisms through which MNi, NPBs and NBUDs originate. Measurement of MNi is also important because entrapment within a micronucleus may cause chromosomes to shatter and, after nuclear reintegration, become rearranged. Additionally, leakage of DNA from MNi can stimulate inflammation via the cyclic GMP-AMP Synthase—Stimulator of Interferon Genes (cGAS-STING) DNA sensing mechanism of the innate immune system.

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Section: Shattering Of Chromosomes In Mni and Their Subsequent Hypmentioning

confidence: 99%

Section: Shattering Of Chromosomes In Mni and Their Subsequent Hypmentioning

confidence: 99%

Cytokinesis-Block Micronucleus Cytome Assay Evolution into a More Comprehensive Method to Measure Chromosomal Instability

Fenech

2020

Genes

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“…35,36 The precise reason for asynchronous DNA replication is not known, although it has been observed in several cell types. 37,38 It is proposed that micronuclei may have poorly functioning membrane, 39 which would affect the replication by a variety of means including DNA replication protein import and DNA organization. 40 In addition, if the DNA is damaged in the micronucleus, then DNA replication might be delayed, and if it is delayed to the point when the cell undergoes mitosis, DNA could be further damaged.…”

Section: Micronuclei Cause Additional Damage To Dnamentioning

confidence: 99%

Cancer cells that survive checkpoint adaptation contain micronuclei that harbor damaged DNA

Lewis

Golsteyn

2016

Cell Cycle

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We have examined the relationship between checkpoint adaptation (mitosis with damaged DNA) and micronuclei. Micronuclei in cancer cells are linked to genomic change, and may induce chromothripsis (chromosome shattering). We measured the cytotoxicity of the cancer drug cisplatin in M059K (glioma fibroblasts, IC50 15 mM). Nearly 100% of M059K cells were positive for histone gH2AX staining after 48 h treatment with a cytotoxic concentration of cisplatin. The proportion of micronucleated cells, as confirmed by microscopy using DAPI and lamin A/C staining, increased from 24% to 48%, and the total micronuclei in surviving cells accumulated over time. Promoting entry into mitosis with a checkpoint inhibitor increased the number of micronuclei in cells whereas blocking checkpoint adaptation with a Cdk inhibitor reduced the number of micronuclei. Interestingly, some micronuclei underwent asynchronous DNA replication, relative to the main nuclei, as measured by deoxy-bromo-uracil (BrdU) staining. These micronuclei stained positive for histone gH2AX, which was linked to DNA replication, suggesting that micronuclei arise from checkpoint adaptation and that micronuclei may continue to damage DNA. By contrast the normal cell line WI-38 did not undergo checkpoint adaptation when treated with cisplatin and did not show changes in micronuclei number. These data reveal that the production of micronuclei by checkpoint adaptation is part of a process that contributes to genomic change.

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“…Nevertheless, the exact mechanism underlying the transformation of clustered DNA lesions into such chromosomal alterations is not yet clearly understood. Based on our previously published evidence on the dynamics of chromatin condensation changes in transforming DNA lesions with chromatin decompaction at their sites into visual breaks [41,42,63], we propose here that high-LET radiation induces not only clustered DNA lesions, but also physical perturbation of the chromatin organization and persistent chromatin decompaction at the sites of clustered DNA lesions. This dual action of energetic nuclei on DNA and chromatin is a key characteristic of high-LET radiation and can translate into localized chromosome shattering in a one-off event, by the dynamics of chromatin condensation during the cell cycle.…”

Section: Our Model: Clustered Dna Lesions Are Transformed Through Chrmentioning

confidence: 71%

Interphase Cytogenetic Analysis of G0 Lymphocytes Exposed to α-Particles, C-Ions, and Protons Reveals their Enhanced Effectiveness for Localized Chromosome Shattering—A Critical Risk for Chromothripsis

Pantelias

Zafiropoulos

Cherubini

et al. 2020

Cancers

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For precision cancer radiotherapy, high linear energy transfer (LET) particle irradiation offers a substantial advantage over photon-based irradiation. In contrast to the sparse deposition of low-density energy by χ- or γ-rays, particle irradiation causes focal DNA damage through high-density energy deposition along the particle tracks. This is characterized by the formation of multiple damage sites, comprising localized clustered patterns of DNA single- and double-strand breaks as well as base damage. These clustered DNA lesions are key determinants of the enhanced relative biological effectiveness (RBE) of energetic nuclei. However, the search for a fingerprint of particle exposure remains open, while the mechanisms underlying the induction of chromothripsis-like chromosomal rearrangements by high-LET radiation (resembling chromothripsis in tumors) await to be elucidated. In this work, we investigate the transformation of clustered DNA lesions into chromosome fragmentation, as indicated by the induction and post-irradiation repair of chromosomal damage under the dynamics of premature chromosome condensation in G0 human lymphocytes. Specifically, this study provides, for the first time, experimental evidence that particle irradiation induces localized shattering of targeted chromosome domains. Yields of chromosome fragments and shattered domains are compared with those generated by γ-rays; and the RBE values obtained are up to 28.6 for α-particles (92 keV/μm), 10.5 for C-ions (295 keV/μm), and 4.9 for protons (28.5 keV/μm). Furthermore, we test the hypothesis that particle radiation-induced persistent clustered DNA lesions and chromatin decompaction at damage sites evolve into localized chromosome shattering by subsequent chromatin condensation in a single catastrophic event—posing a critical risk for random rejoining, chromothripsis, and carcinogenesis. Consistent with this hypothesis, our results highlight the potential use of shattered chromosome domains as a fingerprint of high-LET exposure, while conforming to the new model we propose for the mechanistic origin of chromothripsis-like rearrangements.

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Stress induced by premature chromatin condensation triggers chromosome shattering and chromothripsis at DNA sites still replicating in micronuclei or multinucleate cells when primary nuclei enter mitosis

Cited by 36 publications

References 28 publications

Cytokinesis-Block Micronucleus Cytome Assay Evolution into a More Comprehensive Method to Measure Chromosomal Instability

Cytokinesis-Block Micronucleus Cytome Assay Evolution into a More Comprehensive Method to Measure Chromosomal Instability

Cancer cells that survive checkpoint adaptation contain micronuclei that harbor damaged DNA

Interphase Cytogenetic Analysis of G0 Lymphocytes Exposed to α-Particles, C-Ions, and Protons Reveals their Enhanced Effectiveness for Localized Chromosome Shattering—A Critical Risk for Chromothripsis

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