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.
MeSH terms
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Adenosine Triphosphatases / chemistry
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Adenosine Triphosphatases / metabolism
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / isolation & purification
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Antineoplastic Agents / pharmacology*
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Biological Products / chemistry
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Biological Products / isolation & purification
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Biological Products / pharmacology*
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Cell Survival / drug effects
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DNA Helicases / chemistry
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DNA Helicases / metabolism*
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / metabolism*
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Diterpenes / chemistry
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Diterpenes / isolation & purification
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Diterpenes / pharmacology*
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Dose-Response Relationship, Drug
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Drugs, Chinese Herbal / chemistry
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Drugs, Chinese Herbal / isolation & purification
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Drugs, Chinese Herbal / pharmacology
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Epoxy Compounds / chemistry
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Epoxy Compounds / isolation & purification
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Epoxy Compounds / pharmacology
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HeLa Cells
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Humans
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Phenanthrenes / chemistry
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Phenanthrenes / isolation & purification
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Phenanthrenes / pharmacology*
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Protein Binding
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Protein Subunits / chemistry
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Protein Subunits / metabolism
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RNA Polymerase II / genetics
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RNA Polymerase II / metabolism
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Transcription Factor TFIIH / chemistry
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Transcription Factor TFIIH / metabolism*
Substances
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Antineoplastic Agents
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Biological Products
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DNA-Binding Proteins
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Diterpenes
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Drugs, Chinese Herbal
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Epoxy Compounds
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Phenanthrenes
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Protein Subunits
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XPBC-ERCC-3 protein
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Transcription Factor TFIIH
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triptolide
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RNA Polymerase II
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Adenosine Triphosphatases
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DNA Helicases
Associated data
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PubChem-Substance/103911626
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PubChem-Substance/103911627
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PubChem-Substance/103911628
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PubChem-Substance/103911629
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PubChem-Substance/103911630
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PubChem-Substance/103911631
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PubChem-Substance/103911632
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PubChem-Substance/103911633
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PubChem-Substance/103911634
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PubChem-Substance/103911635
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PubChem-Substance/103911636