Xeroderma pigmentosum group A-complementing protein (XPA) (XPA)

Xeroderma pigmentosum group A-complementing protein (XPA) is a 273-amino acid scaffold protein that plays a central and indispensable role in the eukaryotic nucleotide excision repair (NER) pathway (UniProt P23025). It contains a highly conserved C4-type zinc finger domain (residues 105-129) within its central globular core that is essential for its structural stability and its ability to bind damaged DNA (PubMed: 32235701). XPA acts as a molecular hub, coordinating the assembly of the NER pre-incision complex by interacting with other key repair factors, including replication protein A (RPA), the ERCC1-XPF endonuclease, and the TFIIH helicase complex (PubMed: 31253769). Mutations in the XPA gene result in the most severe form of Xeroderma Pigmentosum, a genetic disorder characterized by extreme sensitivity to ultraviolet (UV) radiation and a vastly increased risk of skin cancers (Wikipedia). In oncology, XPA is an emerging therapeutic target because its overexpression is frequently linked to resistance against platinum-based chemotherapeutics, such as cisplatin, which induce bulky DNA adducts that XPA helps repair (PubMed: 20373710). Small molecule inhibitors like X80 are being developed to target the XPA zinc finger or its DNA-binding interface, aiming to disrupt the NER pathway and sensitize resistant tumors to DNA-damaging treatments (PubMed: 20103576).

Other names

XPACXP1DNA damage recognition and repair factorXeroderma pigmentosum group A protein

Inhibition of the XPA-DNA interaction or XPA-protein interactions (such as with RPA or ERCC1) to block the nucleotide excision repair (NER) pathway, preventing the repair of DNA lesions and sensitizing cancer cells to DNA-damaging agents.