Critical roles of Rad54 in tolerance to apigenin‑induced Top1‑mediated DNA damage

Zhao,Zilu; Wu,Xiaohua; He,Fang; Xiang,Cuifang; Feng,Xiaoyu; Bai,Xin; Liu,Xin; Zhao,Jingxia; Takeda,Shunichi; Qing,Yong

doi:10.3892/etm.2021.9936

Critical roles of Rad54 in tolerance to apigenin‑induced Top1‑mediated DNA damage

Authors:
- Zilu Zhao
- Xiaohua Wu
- Fang He
- Cuifang Xiang
- Xiaoyu Feng
- Xin Bai
- Xin Liu
- Jingxia Zhao
- Shunichi Takeda
- Yong Qing
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Affiliations: Department of Pharmacology, Key Laboratory of Drug‑Targeting and Drug Delivery Systems of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, P.R. China, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China, Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606‑8501, Japan
Published online on: March 18, 2021 https://doi.org/10.3892/etm.2021.9936
Article Number: 505

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Abstract

Apigenin (APG), a flavone sub‑class of flavonoids, possesses a diverse range of biological activities, including anti‑cancer and anti‑inflammatory effects. Previous studies identified the genotoxicity of APG in certain cancer cells, which may be associated with its anticancer effect. However, the DNA damage repair mechanism induced by APG has remained elusive. In order to clarify the molecular mechanisms, the present study determined the toxicity of APG to the wild‑type (WT) DT40 chicken B‑lymphocyte cell line, as well as to DT40 cells with deletions in various DNA repair genes, and their sensitivities were compared. It was demonstrated that cells deficient of Rad54, a critical homologous recombination gene, were particularly sensitive to APG. Cell‑cycle analysis demonstrated that APG caused an increase in the G₂/M‑phase population of Rad54^‑/‑ cells that was greater than that in WT cells. Furthermore, it was demonstrated by immunofluorescence assay that Rad54^‑/‑ cells exhibited significantly increased numbers of γ‑phosphorylated H2AX variant histone foci and chromosomal aberrations compared to the WT cells in response to APG. Of note, the in vitro complex of enzyme assay indicated that APG induced increased topoisomerase I (Top1) covalent protein DNA complex in Rad54^‑/‑ cells compared to WT cells. Finally, these results were verified using the TK6 human lymphoblastoid cell line and it was demonstrated that, as for DT40 cells, Rad54 deficiency sensitized TK6 cells to APG. The present study demonstrated that Rad54 was involved in the repair of APG‑induced DNA damage, which was associated with Top1 inhibition.

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