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XPB, a subunit of TFIIH, is a target of the natural product triptolide

Nature Chemical Biology volume 7, pages 182–188 (2011)Cite this article

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Abstract

Triptolide (1) is a structurally unique diterpene triepoxide isolated from a traditional Chinese medicinal plant with anti-inflammatory, immunosuppressive, contraceptive and antitumor activities. Its molecular mechanism of action, however, has remained largely elusive to date. We report that triptolide covalently binds to human XPB (also known as ERCC3), a subunit of the transcription factor TFIIH, and inhibits its DNA-dependent ATPase activity, which leads to the inhibition of RNA polymerase II–mediated transcription and likely nucleotide excision repair. The identification of XPB as the target of triptolide accounts for the majority of the known biological activities of triptolide. These findings also suggest that triptolide can serve as a new molecular probe for studying transcription and, potentially, as a new type of anticancer agent through inhibition of the ATPase activity of XPB.

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Figure 1: Triptolide is a new type of inhibitor of RNAPII-mediated transcription.
Figure 2: Triptolide inhibits TFIIH-dependent basal transcription and nucleotide excision repair.
Figure 3: Triptolide inhibits the DNA-dependent ATPase activity of TFIIH without affecting its DNA helicase activity.
Figure 4: Triptolide binds covalently to XPB subunit of TFIIH and correlation between inhibition of TFIIH ATPase activity and inhibition of cell proliferation by triptolide analogs.

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Acknowledgements

This work was supported by discretionary funds (J.O.L.). We are grateful to A. Gnatt (University of Maryland) for a kind gift of purified RNAPII and B. Sollner-Webb (Johns Hopkins University) for plasmids. We thank D. Yang for earlier support of this project. We thank P. Cole, J. Corden, J. Stivers and members of the Liu lab for helpful suggestions.

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Authors and Affiliations

  1. Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Denis V Titov, Qing-Li He, Shridhar Bhat, Woon-Kai Low, Yongjun Dang & Jun O Liu

  2. Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado, USA

    Benjamin Gilman, Jennifer F Kugel & James A Goodrich

  3. Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA

    Michael Smeaton & Paul S Miller

  4. Charles A. Dana Research Institute for Scientists Emeriti, Drew University, Madison, New Jersey, USA

    Arnold L Demain

  5. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Jun O Liu

  6. Present: Department of Pharmaceutical Sciences, College of Pharmacy, St. John's University, Queens, New York, USA (W.-K.L.).,

    Woon-Kai Low

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Contributions

D.V.T., J.A.G., P.S.M. and J.O.L. designed the experiments. D.V.T., B.G., Q.-L.H., S.B., W.-K.L. and M.S. performed the experiments. W.-K.L., A.L.D., P.S.M., J.F.K., Y.D. and J.A.G. contributed reagents. D.V.T. and J.O.L. wrote the manuscript.

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Correspondence to Jun O Liu.

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Titov, D., Gilman, B., He, QL. et al. XPB, a subunit of TFIIH, is a target of the natural product triptolide. Nat Chem Biol 7, 182–188 (2011). https://doi.org/10.1038/nchembio.522

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