Excision repair cross-complementation group 5 – Replication protein A complex (ERCC5-RPA)

The ERCC5-RPA complex is a vital protein-protein interaction within the Nucleotide Excision Repair (NER) pathway, responsible for maintaining genomic stability by repairing bulky DNA lesions such as those induced by UV radiation or platinum-based chemotherapy. ERCC5, also known as XPG, is a structure-specific endonuclease that executes the 3' incision of the damaged DNA strand, while Replication Protein A (RPA) is a heterotrimeric protein that binds and stabilizes single-stranded DNA (ssDNA) intermediates. RPA plays a crucial role in recruiting ERCC5 to the repair site and stimulating its catalytic activity through direct physical interaction. In the context of oncology, this complex is a significant therapeutic target because its inhibition can selectively sensitize cancer cells to DNA-damaging agents and overcome platinum resistance. Mutations in the ERCC5 gene are linked to severe genetic disorders, including Xeroderma pigmentosum group G and Cockayne syndrome, which are characterized by extreme sun sensitivity and developmental defects. Current research focuses on developing small molecule inhibitors, such as HAMNO, that disrupt the RPA-ERCC5 interface or RPA's DNA-binding capacity to exploit the high replication stress inherent in many tumor types.

Other names

XPG-RPA complexERCC5-RFA complexXeroderma pigmentosum group G – Replication protein A complexERCC5-RPA interaction

Inhibition of protein-protein interaction between ERCC5 and RPA to prevent recruitment and stimulation of endonuclease activity; inhibition of RPA-ssDNA binding to disrupt the nucleotide excision repair (NER) pathway and sensitize cells to DNA-damaging agents.