DNA excision repair protein ERCC-3 (ERCC3) (ERCC3)

DNA excision repair protein ERCC-3 (ERCC3), also known as XPB, is an ATP-dependent DNA helicase and a core component of the TFIIH basal transcription factor complex. It plays a dual role in cellular maintenance: it is essential for the initiation of RNA polymerase II-mediated transcription and serves as a critical subunit in the Nucleotide Excision Repair (NER) pathway, where it unwinds the DNA helix around damage sites (Alekseev et al., 2014). ERCC3 has become a focal point in precision oncology through its interaction with the drug spironolactone, which acts as a molecular glue to induce the ubiquitination and subsequent proteasomal degradation of the protein (Shah et al., 2019). This degradation effectively disables the NER pathway, creating a therapeutic window for DNA-damaging agents. A prominent application of this mechanism involves LP-184, a prodrug that is bioactivated by Prostaglandin reductase 1 (PTGR1) to form lethal DNA adducts. In tumor cells with high PTGR1 expression, the combination of LP-184 and spironolactone results in a synergistic effect where LP-184 induces extensive DNA damage and spironolactone prevents its repair by depleting ERCC3, leading to selective cancer cell death (Kulkarni et al., 2022). This strategy exploits the synthetic lethality between high PTGR1-driven damage and the loss of NER-mediated repair.

Other names

XPBXeroderma pigmentosum group B-complementing proteinTFIIH basal transcription factor complex helicase subunit ERCC3BTF2P89DNA repair helicase ERCC3

Spironolactone induces the proteasomal degradation of ERCC3, which inhibits the Nucleotide Excision Repair (NER) pathway and prevents the repair of DNA damage induced by agents like LP-184 (Shah et al., 2019; Kulkarni et al., 2022).