DNA excision repair protein ERCC3 (ERCC3)

DNA excision repair protein ERCC3, also commonly referred to as XPB, is an ATP-dependent 3'-5' DNA helicase that serves as a vital subunit of the general transcription factor IIH (TFIIH) complex (UniProt P19447). It plays a dual critical role in cellular maintenance: it is essential for the initiation of RNA polymerase II-mediated transcription by facilitating the opening of the DNA promoter, and it is a key component of the nucleotide excision repair (NER) pathway, where it helps unwind DNA around bulky lesions (PubMed: 22635457). Mutations in the ERCC3 gene are classically associated with rare autosomal recessive disorders such as Xeroderma pigmentosum, Cockayne syndrome, and Trichothiodystrophy, which are characterized by extreme sensitivity to ultraviolet radiation and developmental abnormalities (NCBI Gene: 2071). In modern drug discovery, ERCC3 has gained prominence as a target for anticancer therapy; the natural product triptolide and its clinical-stage water-soluble prodrug, Minnelide, exert potent antitumor effects by covalently binding to ERCC3 and inhibiting its ATPase activity (PubMed: 21248061). This inhibition triggers a rapid decrease in cellular mRNA levels and induces apoptosis, particularly in transcriptionally addicted cancer cells, making it an attractive target for aggressive malignancies like pancreatic cancer.

Other names

Xeroderma pigmentosum group B-complementing proteinXPBBasic transcription factor 2 89 kDa subunitBTF2 p89TFIIH 89 kDa subunitATP-dependent DNA helicase ERCC3

Covalent inhibition of the ATPase activity of the ERCC3/XPB subunit of TFIIH, leading to the inhibition of RNA polymerase II-mediated transcription and nucleotide excision repair.