Benzene metabolite hydroquinone promotes DNA homologous recombination repair via the NF-κB pathway.

Abstract

Benzene, a widespread environmental pollutant, induces DNA double-strand breaks (DSBs) and DNA repair, which may further lead to oncogenic mutations, chromosomal rearrangements and leukemogenesis. However, the molecular mechanisms underlying benzene-induced DNA repair and carcinogenesis remain unclear. The human osteosarcoma cell line (U2OS/DR-GFP), which carries a GFP-based homologous recombination (HR) repair reporter, was treated with hydroquinone, one of the major benzene metabolites, to identify the potential effects of benzene on DSB HR repair. RNA-sequencing was further employed to identify the potential key pathway that contributed to benzene-initiated HR repair. We found that treatment with hydroquinone induced a significant increase in HR. NF-κB pathway, which plays a critical role in carcinogenesis in multiple tumors, was significantly activated in cells recovered from hydroquinone treatment. Furthermore, the upregulation of NF-κB by hydroquinone was also found in human hematopoietic stem and progenitor cells. Notably, the inhibition of NF-κB activity by small molecule inhibitors (QNZ and JSH-23) significantly reduced the frequency of hydroquinone-initiated HR (-1.36- and -1.77-fold, respectively, P < 0.01). Our results demonstrate an important role of NF-κB activity in promoting HR repair induced by hydroquinone. This finding sheds light on the underlying mechanisms involved in benzene-induced genomic instability and leukemogenesis and may contribute to the larger exploration of the influence of other environmental pollutants on carcinogenesis.

• Authors: Xuejing Yang, Yedan Lu, Fuhong He, Fenxia Hou, Caihong Xing, Peiyu Xu, Qian-Fei Wang
• Journal: Carcinogenesis (Carcinogenesis) Vol. 40 Issue 8 Pg. 1021-1030 (08 22 2019) ISSN: 1460-2180 [Electronic] England
• PMID: 30770924 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• 4-methyl-N1-(3-phenylpropyl)benzene-1,2-diamine
• Hydroquinones
• NF-kappa B
• Phenylenediamines
• Small Molecule Libraries
• Benzene
• hydroquinone

Topics

• Benzene (metabolism, toxicity)
• Carcinogenesis (drug effects, genetics)
• Cell Line
• DNA Breaks, Double-Stranded (drug effects)
• DNA Repair (drug effects)
• Hematopoietic Stem Cells
• Homologous Recombination (drug effects, genetics)
• Humans
• Hydroquinones (metabolism, toxicity)
• Mutation (drug effects)
• NF-kappa B (genetics)
• Phenylenediamines (pharmacology)
• RNA-Seq
• Small Molecule Libraries (pharmacology)