A mechanism for 1,4-Benzoquinone-induced genotoxicity

Son, Mi‐Young; Deng, Chu Xia; Hoeijmarkers, Jan H.; Rebel, Vivienne I.; Hasty, Paul

doi:10.18632/oncotarget.10184

Cited by 19 publications

(11 citation statements)

References 85 publications

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“…To further investigate the structural features that TOP2 recognizes, and to identify factors which influence such features, will change how we evaluate the effect of many anti-TOP2 chemotherapeutic agents. In addition, environmental agents like benzene ( 88 ) and phytochemicals in food and natural products ( 89 ) are known to generate TOP2-induced breaks, and identifying regions prone to these stresses will have a broad impact on our understanding of human genome instability.…”

Section: Discussionmentioning

confidence: 99%

Topoisomerase II contributes to DNA secondary structure-mediated double-stranded breaks

Szlachta

Manukyan

Raimer

et al. 2020

Nucleic Acids Research

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Abstract DNA double-stranded breaks (DSBs) trigger human genome instability, therefore identifying what factors contribute to DSB induction is critical for our understanding of human disease etiology. Using an unbiased, genome-wide approach, we found that genomic regions with the ability to form highly stable DNA secondary structures are enriched for endogenous DSBs in human cells. Human genomic regions predicted to form non-B-form DNA induced gross chromosomal rearrangements in yeast and displayed high indel frequency in human genomes. The extent of instability in both analyses is in concordance with the structure forming ability of these regions. We also observed an enrichment of DNA secondary structure-prone sites overlapping transcription start sites (TSSs) and CCCTC-binding factor (CTCF) binding sites, and uncovered an increase in DSBs at highly stable DNA secondary structure regions, in response to etoposide, an inhibitor of topoisomerase II (TOP2) re-ligation activity. Importantly, we found that TOP2 deficiency in both yeast and human leads to a significant reduction in DSBs at structure-prone loci, and that sites of TOP2 cleavage have a greater ability to form highly stable DNA secondary structures. This study reveals a direct role for TOP2 in generating secondary structure-mediated DNA fragility, advancing our understanding of mechanisms underlying human genome instability.

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Section: Discussionmentioning

confidence: 99%

Topoisomerase II contributes to DNA secondary structure-mediated double-stranded breaks

Szlachta

Manukyan

Raimer

et al. 2020

Nucleic Acids Research

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“…1,4-BQ increased the DNA damage in both K562-PTP4A3 − cells and K562-NC cells in a dose-dependent manner. 1,4-BQ could cause DNA damage through suppressing type 1 topoisomerases [41]. DNA damage was higher in K562-PTP4A3 − cells than K562-NC cells at a low dose 1,4-BQ (10 µM).…”

Section: Discussionmentioning

confidence: 94%

PTP4A3, A Novel Target Gene of HIF-1alpha, Participates in Benzene-Induced Cell Proliferation Inhibition and Apoptosis through PI3K/AKT Pathway

Sun

et al. 2020

IJERPH

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Benzene, a commonly used chemical, has been confirmed to specifically affect the hematopoietic system as well as overall human health. PTP4A3 is overexpressed in leukemia cells and is related to cell proliferation. We previously found that HIF-1alpha was involved in benzene toxicity and PTP4A3 may be the target gene of HIF-1alpha via ChIP-seq. The aim of this study is to confirm the relationship between HIF-1alpha and PTP4A3 in benzene toxicity, as well as the function of PTP4A3 on cell toxicity induced by 1,4-benzoquinone (1,4-BQ). Our results indicate that HIF-1alpha could regulate PTP4A3 with in vivo and in vitro experiments. A cell line with suppressed PTP4A3 was established to investigate the function of PTP4A3 in 1,4-BQ toxicity in vitro. The results revealed that cell proliferation inhibition was more aggravated in PTP4A3 low-expression cells than in the control cells after 1,4-BQ treatment. The relative oxygen species (ROS) significantly increased in cells with inhibited PTP4A3, while the rise was inferior to the control cells at the 20 μM 1,4-BQ group. An increase in DNA damage was seen in PTP4A3 down-regulated cells at the 10 μM 1,4-BQ group, whereas the results reversed at the concentration of 20 μM. Moreover, the apoptosis rate increased higher in down-regulated PTP4A3 cells after 1,4-BQ exposure. In addition, PI3K/AKT pathway was significantly restrained in cells with inhibited PTP4A3 after 1,4-BQ treatment. Our results indicate that HIF-1alpha may regulate PTP4A3 to be involved in benzene toxicity. Inhibition of PTP4A3 could aggravate cell proliferation suppression and apoptosis by regulating PI3K/AKT pathway after 1,4-BQ treatment.

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“…For the molecular and cellular mechanisms underlying BQ hematotoxicity, several molecular pathways have been proposed, such as type 1 topoisomerases (Son et al, 2016). It has been shown that BQ modulates the fate of HSPCs by altering the self-renewal- and differentiation-related genes, such as Bmi-1 and GATA3 (Chow et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Previous in vitro studies have shown that exposure of murine hematopoietic stem and progenitor cells (HSPCs) to BQ interferes with their physiological properties and changes their clonogenic potency by altering genes for apoptosis, DNA repair, cell cycle, self-renewal and differentiation (Chow et al, 2018; Faiola et al, 2004). Son et al (2016) analyzed the impact that BQ exposure has on DNA-repair-defective mouse embryonic stem cells. They proposed that BQ suppresses type 1 topoisomerases to inhibit replication fork restart and progression, leading to chromosomal instability that has the potential to cause hematopoietic disorders.…”

Section: Introductionmentioning

confidence: 99%

Establishment of a zebrafish hematological disease model induced by 1,4-benzoquinone

Zhang

Tan

et al. 2019

Disease Models &Amp; Mechanisms

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Benzene exposure is associated with various hematological disorders, in particular leukemia. The reactive metabolite of benzene, 1,4-benzoquinone (BQ), generated in bone marrow, is suggested to be a key molecule in mediating benzene-induced hematotoxicity and carcinogenicity. However, its pathogenic role remains largely unknown due to a lack of suitable vertebrate whole-organism models. Here, we present an in vivo study to reveal the effect of BQ exposure on hematotoxicity in zebrafish. From embryonic stages to adulthood, BQ exposure suppressed erythroid and lymphoid hematopoiesis but led to abnormal accumulation of myeloid cells and precursors, which resembles benzene-induced cytopenia and myeloid dysplasia in humans. This myeloid expansion is caused by granulocyte, but not macrophage, lineage, emphasizing the significant role of lineage specificity in BQ-mediated hematopoietic toxicity. Analysis of the c-myb (also known as myb ) - deficient mutant cmyb hkz3 revealed that BQ induced neutrophilia in a c-myb -dependent manner, demonstrating that c-myb is a key intrinsic mediator of BQ hematotoxicity. Our study reveals that BQ causes lineage-specific hematotoxicity in zebrafish from embryonic stages to adulthood. Since c-myb is indispensable for BQ to induce neutrophilia, c-myb could serve as a potential drug target for reversing BQ hematotoxicity.

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A mechanism for 1,4-Benzoquinone-induced genotoxicity

Cited by 19 publications

References 85 publications

Topoisomerase II contributes to DNA secondary structure-mediated double-stranded breaks

Topoisomerase II contributes to DNA secondary structure-mediated double-stranded breaks

PTP4A3, A Novel Target Gene of HIF-1alpha, Participates in Benzene-Induced Cell Proliferation Inhibition and Apoptosis through PI3K/AKT Pathway

Establishment of a zebrafish hematological disease model induced by 1,4-benzoquinone

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