2. Academic Validation
  3. Triptolide impairs genome integrity by directly blocking the enzymatic activity of DNA-PKcs in human cells

Triptolide impairs genome integrity by directly blocking the enzymatic activity of DNA-PKcs in human cells

  • Biomed Pharmacother. 2020 Sep;129:110427. doi: 10.1016/j.biopha.2020.110427.
Bailian Cai 1,  Zhiyi Hu 1,  Huanyin Tang 2,  Zhangsen Hu 2,  Zhiyong Mao 3,  Binya Liu 1,  Xiaojun Xu 4,  Ying Jiang 5,  Xiaoping Wan 6
Affiliations

Affiliations

  • 1 Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China.
  • 2 Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 3 Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China; Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 4 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].
  • 5 Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. Electronic address: [email protected].
  • 6 Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China; Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. Electronic address: [email protected].
PMID: 32574974 DOI: 10.1016/j.biopha.2020.110427
Abstract

Triptolide is a multi-functional natural small molecular compound extracted from a traditional Chinese medicinal herb. Triptolide and its derivatives exhibit cytotoxicity through inducing DNA damage, therefore increasing sensitivity to DNA-damage based chemotherapy or radiotherapy in different types of cells. However, the regulatory mechanism of genotoxicity by triptolide, and the loss of genome integrity induced by triptolide are not fully understood. Here, we measured the effects of triptolide on genome integrity in a human fibroblast line HCA2-hTERT using the neutral comet assay. We demonstrated that treating cells with triptolide induced genomic instability in HCA2-hTERT cells. Furthermore, we observed the accumulation of γH2AX foci in triptolide treated cells than control cells at 24 h post ionizing radiation. Further mechanistic studies indicated that triptolide inhibited the enzymatic activity of DNA-PKcs, the critical nonhomologous end joining factor. In vitro kinase activity assays showed that triptolide suppressed the kinase activity of DNA-PKcs and molecular docking also predicted a potential interaction between triptolide and DNA-PKcs. As a consequence, we found that triptolide treatment enhanced the interaction between DNA-PKcs and KU80 and hampered the following recruitment of 53BP1. Altogether, our finding provides a new perspective about the toxicity of triptolide in non-cancer cells and highlights the necessity of taking genome effects of triptolide and its derivatives into consideration in the future clinical and research applications.

Keywords

DNA-PKcs; Genome integrity; Non-homologous end joining; Triptolide.

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