ArticleToxicological sciences : an official journal of the Society of Toxicology2015
DNA double-strand breaks by Cr(VI) are targeted to euchromatin and cause ATR-dependent phosphorylation of histone H2AX and its ubiquitination.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 1 of them a synthesis that pooled it.
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Who cites it
32 citing papers in PubMed, 1 synthesis or guideline pooled it, 60 citations in OpenAlex.
- Chromium as a Risk Factor for Breast Cancer: A Meta-Analysis.Asian Pacific journal of cancer prevention : APJCP · 2022Pooled it
- How histone modifications influence cellular radiosensitivity: Pharmaceutically targeting epigenetic regulators as a promising avenue to overcome radioresistance.Acta pharmaceutica Sinica. B · 2025Review
- Particulate hexavalent chromium exposure induces DNA double-strand breaks and inhibits homologous recombination repair in rat and human lung tissues.Chemosphere · 2025Article
- Carcinogenic Mechanisms of Hexavalent Chromium: From DNA Breaks to Chromosome Instability and Neoplastic Transformation.Current environmental health reports · 2024Review
- Chromate Affects Gene Expression and DNA Methylation in Long-Term In Vitro Experiments in A549 Cells.International journal of molecular sciences · 2024Article
- Acute particulate hexavalent chromium exposure induces DNA double-strand breaks and activates homologous recombination repair in rat lung tissue.Toxicological sciences : an official journal of the Society of Toxicology · 2024Article
- Tl(I) and Tl(III)-induce genotoxicity, reticulum stress and autophagy in PC12 Adh cells.Archives of toxicology · 2024Article
- Prolonged particulate hexavalent chromium exposure induces RAD51 foci inhibition and cytoplasmic accumulation in immortalized and primary human lung bronchial epithelial cells.Toxicology and applied pharmacology · 2023Article
- ATR activation by Cr-DNA damage is a major survival response establishing late S and G2 checkpoints after Cr(VI) exposure.Toxicology and applied pharmacology · 2023Article
- Effect of hexavalent chromium on growth performance and metabolism in broiler chicken.Frontiers in veterinary science · 2023Article
- Chemical mechanisms of DNA damage by carcinogenic chromium(VI).Advances in pharmacology (San Diego, Calif.) · 2023Article
- Unveiling the Toxicity of Fine and Nano-Sized Airborne Particles Generated from Industrial Thermal Spraying Processes in Human Alveolar Epithelial Cells.International journal of molecular sciences · 2022Article
- Ascorbate: antioxidant and biochemical activities and their importance for in vitro models.Archives of toxicology · 2021Review
- Hexavalent chromium promotes differential binding of CTCF to its cognate sites in Euchromatin.Epigenetics · 2021Article
- Hexavalent chromium disrupts chromatin architecture.Seminars in cancer biology · 2021Review
- DNA Double-Strand Breaks Induced in Human Cells by Twelve Metallic Species: Quantitative Inter-Comparisons and Influence of the ATM Protein.Biomolecules · 2021Article
- Nuclear and Cytoplasmic Functions of Vitamin C.Chemical research in toxicology · 2020Review
- Chromium Pollution in European Water, Sources, Health Risk, and Remediation Strategies: An Overview.International journal of environmental research and public health · 2020Review
- Molecular and epigenetic mechanisms of Cr(VI)-induced carcinogenesis.Toxicology and applied pharmacology · 2019Review
- Chromium exposure disrupts chromatin architecture upsetting the mechanisms that regulate transcription.Experimental biology and medicine (Maywood, N.J.) · 2019Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Hexavalent chromium is a human respiratory carcinogen that undergoes intracellular activation in vivo primarily via reduction with ascorbate. Replication of Cr-adducted DNA triggers mismatch repair that generates toxic DNA double-strand breaks (DSBs) as secondary lesions. Here, we examined the intranuclear distribution of chromate-induced breaks and a central DSB signaling branch targeting histone H2AX. Using ascorbate-restored cells (H460 human lung epithelial cells, normal human lung and normal mouse embryonic fibroblasts (MEFs)), we found that Cr(VI) produced a typical DSB-associated spectrum of H2AX modifications, including its Ser139-phosphorylated (known as γH2AX) and mono- and diubiquitinated forms. However, whereas canonical DSB signaling relies on ATM, the formation of γH2AX and its ubiquitinated products by Cr(VI) was dependent on ATR kinase. Based on the established mode of ATR activation, this suggests that Cr-induced DSB are not blunt-ended and likely contain single-stranded tails. Confocal imaging with markers of active and inactive chromatin revealed a selective formation of Cr-induced DSB in euchromatin of mouse and human cells. In contrast to DSB, Cr-DNA adducts were produced in both types of chromatin. The euchromatin targeting of Cr-induced DSB makes these lesions particularly dangerous by increasing the probability of deleting active tumor suppressors and producing oncogenic translocations. Accumulation of transcription-inhibiting ubiquitinated forms of γH2AX in euchromatin is expected to contribute to the ability of Cr(VI) to suppress upregulation of inducible genes.
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