DNA lesions sequestered in micronuclei induce a local defective-damage response

Terradas, Mariona; Martı́n, Marga; Tusell, Laura; Genescà, Anna

doi:10.1016/j.dnarep.2009.07.004

Cited by 100 publications

(84 citation statements)

References 43 publications

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“…The DSB marker γH2AX was increased in micronuclei however 53BP1 was absent, consistent with DSB signaling defects (Fig 1f) 5, 6 . Nuclei of NHEJ knockout and DNA-PKi treated cells were morphologically normal despite being replete with DSBs (Fig 1f and 2a).…”

supporting

confidence: 65%

Mitotic progression following DNA damage enables pattern recognition within micronuclei

Harding

Benci

Irianto

et al. 2017

Nature

1,142

780

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Inflammatory gene expression following genotoxic cancer therapy is well documented, yet the events underlying its induction remain poorly understood. Inflammatory cytokines modify the tumor microenvironment by recruiting immune cells and are critical for both local and systemic (abscopal) tumor responses to radiotherapy1. An enigmatic feature of this phenomenon is its delayed onset (days), in contrast to the acute DNA damage responses that occur in minutes to hours. Such dichotomous kinetics implicate additional rate limiting steps that are essential for DNA-damage induced inflammation. Here, we show that cell cycle progression through mitosis following DNA double-strand breaks (DSBs) leads to the formation of micronuclei, which precede activation of inflammatory signaling and are a repository for the pattern recognition receptor cGAS. Inhibiting progression through mitosis or loss of pattern recognition by cGAS-STING impaired interferon signaling. Moreover, STING loss prevented the regression of abscopal tumors in the context of ionizing radiation and immune checkpoint blockade in vivo. These findings implicate temporal modulation of the cell cycle as an important consideration in the context of therapeutic strategies that combine genotoxic agents with immune checkpoint blockade.

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supporting

confidence: 65%

Mitotic progression following DNA damage enables pattern recognition within micronuclei

Harding

Benci

Irianto

et al. 2017

Nature

1,142

780

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“…Moreover, this assay was found to be more sensitive than the comet assay when we compare our results regarding PAHs genotoxicity with published data on the same cell line (Plazar et al, 2007;Winter et al, 2008;Tarantini et al, 2009). Concerning the comparison of the γ-H2AX assay with the micronucleus test, it is now well established that the micronucleus formation correlates well with H2AX phosphorylation (Medvedeva et al, 2007;Terradas et al, 2009;Yoshikawa et al, 2009). …”

Section: Genotoxicity Of Pahs In Human Cell Linesmentioning

confidence: 65%

Comparative potency approach based on H2AX assay for estimating the genotoxicity of polycyclic aromatic hydrocarbons

Audebert

Zeman

Beaudoin

et al. 2012

Toxicology and Applied Pharmacology

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a b s t r a c t a r t i c l e i n f oPolycyclic Aromatic Hydrocarbons (PAHs) constitute a family of over one hundred compounds and can generally be found in complex mixtures. PAHs metabolites cause DNA damage which can lead to the development of carcinogenesis. Toxicity assessment of PAH complex mixtures is currently expressed in terms of toxic equivalents, based on Toxicity Equivalent Factors (TEFs). However, the definition of new TEFs for a large number of PAH could overcome some limitations of the current method and improve cancer risk assessment. The current investigation aimed at deriving the relative potency factors of PAHs, based on their genotoxic effect measured in vitro and analyzed with mathematical models. For this purpose, we used a new genotoxic assay (γH2AX) with two human cell lines (HepG2 and LS-174T) to analyze the genotoxic properties of 13 selected PAHs at low doses after 24 h treatment. The dose-response for genotoxic effects was modeled with a Hill model; equivalency between PAHs at low dose was assessed by applying constraints to the model parameters. In the two cell lines tested, we observed a clear dose-response for genotoxic effects for 11 tested compounds. LS-174T was on average ten times more sensitive than HepG2 towards PAHs regarding genotoxicity. We developed new TEFs, which we named Genotoxic Equivalent Factor (GEF). Calculated GEF for the tested PAHs were generally higher than the TEF usually used. Our study proposed a new in vitro based method for the establishment of relevant TEFs for PAHs to improve cancer risk assessment.

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“…Micronuclei in cancer cells accumulate DNA damage 17–19 and, in Xenopus , DNA damage was shown to trigger apoptosis at the onset of gastrulation 20 . As in cancer cells, micronuclei in t e × l s hybrid embryos often lost envelope integrity and contained damaged DNA (Extended Data Fig.…”

mentioning

confidence: 99%

Paternal chromosome loss and metabolic crisis contribute to hybrid inviability in Xenopus

Gibeaux

Acker

Kitaoka

et al. 2018

Nature

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DNA lesions sequestered in micronuclei induce a local defective-damage response

Cited by 100 publications

References 43 publications

Mitotic progression following DNA damage enables pattern recognition within micronuclei

Mitotic progression following DNA damage enables pattern recognition within micronuclei

Comparative potency approach based on H2AX assay for estimating the genotoxicity of polycyclic aromatic hydrocarbons

Paternal chromosome loss and metabolic crisis contribute to hybrid inviability in Xenopus

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