DNA excision repair protein ERCC-5 – Proliferating cell nuclear antigen complex (ERCC5–PCNA)

The ERCC5–PCNA complex is a critical protein-protein interaction involved in the human nucleotide excision repair (NER) pathway, which identifies and removes bulky DNA lesions caused by UV radiation and chemical mutagens (UniProt P28748). ERCC5, also known as XPG, is a structure-specific endonuclease that provides the 3' incision necessary for lesion excision, while PCNA (Proliferating Cell Nuclear Antigen) serves as a sliding clamp that coordinates the assembly of the repair machinery on DNA (PubMed 9305916). The interaction is mediated by a PCNA-interacting protein (PIP) box in the C-terminus of ERCC5, which facilitates its recruitment to the repair site and ensures the orderly transition from DNA incision to repair synthesis (PubMed 16246722). Mutations in ERCC5 that impair this interaction or the protein's catalytic activity result in severe genetic disorders such as Xeroderma Pigmentosum group G and Cockayne syndrome, characterized by extreme photosensitivity and neurodevelopmental defects (UniProt P28748). In oncology, the ERCC5–PCNA interaction is a target for therapeutic sensitization; disrupting this complex can prevent cancer cells from repairing damage induced by platinum-based chemotherapy or radiation. Small molecule inhibitors of PCNA, such as AOH1996, are currently being investigated for their ability to disrupt these interactions and induce synthetic lethality in tumors with existing DNA repair vulnerabilities (PubMed 37531861).

Other names

XPG–PCNA interactionERCC5–PCNA interactionXPG–PCNA complexDNA excision repair protein ERCC-5 – Proliferating cell nuclear antigen complex

Inhibition of protein-protein interaction between ERCC5 and PCNA, leading to the disruption of the nucleotide excision repair pathway and sensitization of cancer cells to DNA-damaging agents.