ERCC5 encodes a structure-specific endonuclease that plays critical roles in multiple DNA repair pathways. The protein functions primarily in nucleotide excision repair (NER) by making 3' incisions at DNA damage sites and binding repair bubble substrates 1. ERCC5 also participates in transcription-coupled NER, cooperating with ERCC6/CSB to recognize stalled RNA polymerase II and stimulate repair bubble formation 2. Additionally, the enzyme contributes to base excision repair by enhancing DNA glycosylase NTHL1 activity 3 and homologous recombination repair by recruiting RAD51, BRCA2, and PALB2 to damaged DNA sites 4. ERCC5 is essential for maintaining replication fork stability and genomic integrity 1. Mutations in ERCC5 cause xeroderma pigmentosum complementation group G and cerebro-oculo-facio-skeletal syndrome, characterized by DNA repair deficiency and accelerated aging 5. Polymorphisms in ERCC5 are associated with increased cancer risk, particularly for gastric, breast, cervical, esophageal, and laryngeal cancers 6789. In cancer therapy, ERCC5 expression levels may predict treatment response, with increased ERCC5 associated with enhanced efficacy of certain DNA-damaging agents 10.