γH2AX foci on apparently intact mitotic chromosomes: Not signatures of misrejoining events but signals of unresolved DNA damage

Martı́n, Marga; Terradas, Mariona; Hernández, Laia; Genescà, Anna

doi:10.4161/15384101.2014.947786

Cited by 22 publications

(15 citation statements)

References 49 publications

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“…Thus if these incomplete chromosome elements are able to reach cytokinesis, they should be transmitted to daughter cells, as were the persistent IRIF observed in our study. Analyzing metaphase cells, Martin et al reported that persistent IRIF do not seem to co-locate with either telomere-free chromosome ends or misrepaired breaks [41]. It is nonetheless important to note that histone H2AX phosphorylation takes place on serine 139 along the chromosome arms from metaphase to telophase, independently of any DNA damage induced [42][43][44].…”

Section: Discussionmentioning

confidence: 99%

Transmission of persistent ionizing radiation-induced foci through cell division in human primary cells

Vaurijoux

Voisin

Fréneau

et al. 2017

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Unrepaired DNA double-strand breaks (DSBs) induced by ionizing radiation are associated with lethal effects and genomic instability. After the initial breaks and chromatin destabilization, a set of post-translational modifications of histones occurs, including phosphorylation of serine 139 of histone H2AX (γH2AX), which leads to the formation of ionizing radiation-induced foci (IRIF). DSB repair results in the disappearance of most IRIF within hours after exposure, although some remain 24h after irradiation. Their relation to unrepaired DSBs is generally accepted but still controversial. This study evaluates the frequency and kinetics of persistent IRIF and analyzes their impact on cell proliferation. We observed persistent IRIF up to 7 days postirradiation, and more than 70% of cells exposed to 5Gy had at least one of these persistent IRIF 24h after exposure. Moreover we demonstrated that persistent IRIF did not block cell proliferation definitively. The frequency of IRIF was lower in daughter cells, due to asymmetric distribution of IRIF between some of them. We report a positive association between the presence of IRIF and the likelihood of DNA missegregation. Hence, the structure formed after the passage of a persistent IRI focus across the S and G2 phases may impede the correct segregation of the affected chromosome's sister chromatids. The ensuing abnormal resolution of anaphase might therefore cause the nature of IRIF in daughter-cell nuclei to differ before and after the first cell division. The resulting atypical chromosomal assembly may be lethal or result in a gene dosage imbalance and possibly enhanced genomic instability, in particular in the daughter cells.

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Section: Discussionmentioning

confidence: 99%

Transmission of persistent ionizing radiation-induced foci through cell division in human primary cells

Vaurijoux

Voisin

Fréneau

et al. 2017

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…as pointed out recently [285,288], in some conditions, they may also be indicative for unresolved DNA damage that may promote cellular senescence.…”

Section: Biomarkers Relevant For Radiation Dosimetry and Biological Amentioning

confidence: 76%

Progress in low dose health risk research

Averbeck

Salomaa

Bouffler

et al. 2018

Mutation Research/Reviews in Mutation Research

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People are more often exposed to low as opposed to high doses of ionising radiation (IR). Knowledge on the health risks associated with exposures to ionising radiation above 100 mGy is quite well established, while lower dose risks are inferred from higher level exposure information (ICRP). The health risk assessments are mainly based on epidemiological data derived from the atomic bombing of Hiroshima and Nagasaki, medical exposure studies and follow-up studies after nuclear accidents. For the estimation of long-term stochastic radiation health effects (such as cancer) and radiation protection purposes, a linear non-threshold (LNT) model is applied. However, the general validity of the LNT hypothesis for extrapolations from effects of high to low doses (<100 mGy) and low dose-rates (<6 mGy/h) has been questioned as epidemiological studies are statistically limited at low doses and unable to evaluate low dose and low dose-rate health risks (UNSCEAR). Thus, uncertainties on health risks need to be clarified with the help of mechanistic studies. The European Network of Excellence DoReMi (2010-2016) was designed to address some of the existing uncertainties and to identify research lines that are likely to be most informative for low dose risk assessment. The present review reports the results obtained from studies addressing the induction of cancer and non-cancer effects by low dose IR as well as on individual radiation sensitivity. It is shown that low dose and low dose-rate effects are the result of complex network responses including genetic, epigenetic, metabolic and immunological regulation. Evidence is provided for the existence of nonlinear biological responses in the low and medium dose range as well as effects other than the classical DNA damage. Such effects may have a bearing on the quantitative and qualitative judgements on health effects induced by low dose radiations.

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“…HR is activated and works during the S and G2 phases of the cell cycle [ 33 ]. Martin et al showed MRE11 is induced in response to DNA injury and co-localized with γH2AX after irradiation, measured by IF in lymphoblastoid cell lines in vitro [ 34 ]. Choudhry and colleagues examined protein expression of MRE11, RAD50, NBS1, ATM, and H2AX by immunohistochemistry in pretreatment tumor specimens from 179 bladder cancer patients receiving radical radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

Development of a multiparameter flow cytometric assay as a potential biomarker for homologous recombination deficiency in women with high-grade serous ovarian cancer

et al. 2015

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ObjectivesPARP inhibitors (PARPi) are a novel class of drugs with activity in patients with acquired or germline homologous recombination (HR) deficiency-associated high-grade serous ovarian cancer (HGSOC). We hypothesized that measuring γH2AX as an indicator of DNA double-strand breaks (DSB), and MRE11 or RAD51 as an indicator of DSB repair, would reflect HR status and predict response to PARPi-based therapy. Our aim was to develop and use high-throughput multiparametric flow cytometry to quantify γH2AX with MRE11 or RAD51 in PBMCs as a readily available surrogate.MethodsHealthy donor PBMCs were used for assay development and optimization. We validated induction of γH2AX, MRE11 and RAD51 by staining with fluorophore-conjugated antibodies. The multiparameter flow cytometric method was applied to PBMC samples from recurrent HGSOC patients who were treated with PARPi, olaparib and carboplatin.ResultsStimulation was necessary for quantification of a DNA damage response to olaparib/carboplatin in healthy donor PBMCs. The flow cytometric protocol could not distinguish between cytoplasmic and nuclear RAD51, erroneously indicating activation in response to injury. Thus, MRE11 was selected as the marker of DSB repair. PBMCs from 15 recurrent HGSOC patients were then examined. Patients who did not respond to PARPi therapy had a significantly higher pre-treatment level of γH2AX (p = 0.01), and a higher ratio of γH2AX/MRE11 (11.0 [3.5–13.2] v. 3.3 [2.8–9.9], p < 0.03) compared with responders.ConclusionsWe successfully developed and applied a multiparameter flow cytometry assay to measure γH2AX and MRE11 in PBMCs. Prospective studies will be required to validate this surrogate biomarker assay as a potential predictive biomarker of PARPi-based therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0604-z) contains supplementary material, which is available to authorized users.

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γH2AX foci on apparently intact mitotic chromosomes: Not signatures of misrejoining events but signals of unresolved DNA damage

Cited by 22 publications

References 49 publications

Transmission of persistent ionizing radiation-induced foci through cell division in human primary cells

Transmission of persistent ionizing radiation-induced foci through cell division in human primary cells

Progress in low dose health risk research

Development of a multiparameter flow cytometric assay as a potential biomarker for homologous recombination deficiency in women with high-grade serous ovarian cancer

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