Excision repair cross-complementation group 5 – Breast cancer type 1 susceptibility protein interaction (ERCC5 – BRCA1)

Excision repair cross-complementation group 5 (ERCC5, also known as XPG) and Breast cancer type 1 susceptibility protein (BRCA1) are essential components of the cellular DNA damage response (DDR) network, mediating nucleotide excision repair (NER) and homologous recombination (HR), respectively (UniProt; PubMed: 26833090). The physical and functional interaction between ERCC5 and BRCA1 is vital for the coordination of DNA repair pathways; specifically, ERCC5 is involved in the recruitment and subsequent release of BRCA1 at sites of DNA damage to facilitate the transition between repair phases (UniProt; PubMed: 26833090). This interaction is a key determinant of sensitivity to certain anti-cancer agents, most notably trabectedin (Yondelis) and lurbinectedin (Zepzelca) (Molecular Cancer Therapeutics, 2013). Trabectedin acts by binding to the DNA minor groove and trapping the ERCC5-containing NER complex, which generates persistent DNA double-strand breaks that are lethal in cells with HR deficiencies, such as those harboring BRCA1 mutations (Annals of Oncology, 2015). This "synthetic lethality" or "pathway trapping" mechanism makes the ERCC5-BRCA1 axis a critical biomarker signature for predicting therapeutic response in soft tissue sarcomas and ovarian cancers (Frontiers in Oncology, 2022). Clinical studies have demonstrated that high ERCC5 expression combined with low BRCA1 expression (or BRCA1 mutation) serves as a potent predictor of improved progression-free survival in patients treated with these agents (Molecular Cancer Therapeutics, 2013).

Other names

XPG – BRCA1 interactionERCC5 – BRCA1 complexXPG – BRCA1 complexXeroderma pigmentosum group G – Breast cancer type 1 susceptibility protein interaction

Trabectedin and lurbinectedin bind to the DNA minor groove and trap the ERCC5 (XPG) protein within the nucleotide excision repair (NER) complex, creating lethal DNA lesions that are particularly toxic in cells with homologous recombination (HR) deficiency, such as those with BRCA1 mutations.