Xeroderma pigmentosum group B-complementing protein (XPB) (XPB)

Xeroderma pigmentosum group B-complementing protein (XPB), also known as ERCC3, is an essential ATP-dependent DNA helicase and a core subunit of the Transcription Factor IIH (TFIIH) complex [3, 13]. It plays a dual role in the cell: it is required for the initiation of RNA polymerase II-mediated transcription by unwinding the DNA at the promoter, and it is critical for Nucleotide Excision Repair (NER) by opening the DNA around lesions [1, 9]. Mutations in the XPB gene are associated with severe genetic disorders, including Xeroderma pigmentosum, Cockayne syndrome, and Trichothiodystrophy, which are characterized by extreme sun sensitivity and developmental defects [12, 14]. In the context of oncology, XPB has emerged as a significant therapeutic target because its inhibition leads to a global reduction in transcription and the impairment of DNA repair, making cancer cells particularly vulnerable to apoptosis [4, 5]. The natural product triptolide and its derivatives, such as the prodrug Minnelide, are potent covalent inhibitors of XPB's ATPase activity, demonstrating broad-spectrum anticancer activity in preclinical and clinical studies [2, 3]. Triptolide binding also triggers the degradation of the Rpb1 subunit of RNA polymerase II, further contributing to its cytotoxic effects [5]. However, the essential nature of XPB in normal cellular processes presents challenges for drug development, necessitating careful management of systemic toxicity and the pursuit of tumor-selective delivery strategies [1, 4].

Other names

ERCC3Excision repair cross-complementing rodent repair deficiency complementation group 3BTF2 p89TFIIH 89 kDa subunitDNA repair helicase XPBBasic transcription factor 2 89 kDa subunit

Covalent inhibition of the DNA-dependent ATPase activity of XPB, which prevents the opening of the DNA duplex at promoters and repair sites, thereby inhibiting RNA polymerase II-mediated transcription initiation and nucleotide excision repair (NER).