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

• Published in: Nature chemical biology Vol. 7; no. 3; pp. 182 - 188
• Main Authors: Liu, Jun O, Titov, Denis V, Gilman, Benjamin, He, Qing-Li, Bhat, Shridhar, Low, Woon-Kai, Dang, Yongjun, Smeaton, Michael, Demain, Arnold L, Miller, Paul S, Kugel, Jennifer F, Goodrich, James A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2011; Nature Publishing Group
• Subjects: 631/154/555; 631/92/349; 631/92/609; Adenosine triphosphatase; Adenosine Triphosphatases - chemistry; Adenosine Triphosphatases - metabolism; Antineoplastic Agents - chemistry; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Biochemical Engineering; Biochemistry; Biological Products - chemistry; Biological Products - isolation & purification; Biological Products - pharmacology; Bioorganic Chemistry; Cell Biology; Cell Survival - drug effects; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Chinese medicine; Deoxyribonucleic acid; Diterpenes - chemistry; Diterpenes - isolation & purification; Diterpenes - pharmacology; DNA; DNA Helicases - chemistry; DNA Helicases - metabolism; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; Drugs, Chinese Herbal - chemistry; Drugs, Chinese Herbal - isolation & purification; Drugs, Chinese Herbal - pharmacology; Epoxy Compounds - chemistry; Epoxy Compounds - isolation & purification; Epoxy Compounds - pharmacology; Eukaryotes; Flowers & plants; HeLa Cells; Humans; Medicinal plants; Phenanthrenes - chemistry; Phenanthrenes - isolation & purification; Phenanthrenes - pharmacology; Protein Binding; Protein Subunits - chemistry; Protein Subunits - metabolism; RNA Polymerase II - genetics; RNA Polymerase II - metabolism; Transcription Factor TFIIH - chemistry; Transcription Factor TFIIH - metabolism
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.522

Triptolide is a bioactive natural product isolated from plants used in traditional Chinese medicine. A target identification approach shows that triptolide modulates RNA transcription and nucleotide excision repair by covalent binding to the XPB subunit of the transcription factor TFIIH. 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.