Transcription factor IIH subunit XPB (XPB)

Transcription factor IIH subunit XPB (also known as ERCC3) is an essential ATP-dependent DNA translocase and a core component of the multi-subunit TFIIH complex [2, 10]. It plays a dual role in cellular maintenance: it is required for the initiation of RNA polymerase II-mediated transcription by facilitating promoter opening, and it is a critical factor in the Nucleotide Excision Repair (NER) pathway, where it unwinds DNA around bulky lesions [5, 15]. Mutations in the ERCC3 gene are associated with severe genetic disorders such as Xeroderma pigmentosum, Cockayne syndrome, and Trichothiodystrophy, which are characterized by extreme sensitivity to ultraviolet radiation and developmental abnormalities [4, 18]. In the context of oncology, XPB has emerged as a significant therapeutic target because its inhibition can simultaneously disrupt transcription and DNA repair, leading to selective toxicity in rapidly dividing cancer cells [1, 8]. Small molecules such as triptolide and its water-soluble prodrug Minnelide covalently bind to XPB and inhibit its ATPase activity, demonstrating potent antitumor activity in various malignancies, including pancreatic cancer and multiple myeloma [6, 9]. Additionally, the drug spironolactone has been found to induce the degradation of XPB, further highlighting its potential as a druggable node in the DNA damage response [14].

Other names

ERCC3Excision repair cross-complementation group 3BTF2GTF2HRAD25TTD2Ssl2General transcription and DNA repair factor IIH helicase/translocase subunit XPB

Triptolide and its prodrug Minnelide covalently bind to the XPB subunit and inhibit its DNA-dependent ATPase activity, thereby blocking transcription initiation and nucleotide excision repair [6, 9]. Spironolactone induces the proteasomal degradation of the XPB protein, leading to a reduction in TFIIH-mediated DNA repair and transcription [14].