ERCC6 is an essential ATP-dependent chr10 remodeling factor that functions primarily in transcription-coupled nucleotide excision repair (TC-NER) 1. It recognizes RNA polymerase II stalled at DNA lesions and recruits ERCC8/CSA and TFIIH to initiate damage excision, while locally modifying DNA conformation to facilitate repair 1. Beyond TC-NER, ERCC6 functions in double-strand break (DSB) repair by promoting homologous recombination while inhibiting non-homologous end joining, and activates ATM/CHEK2-dependent DNA damage checkpoints [UniProt references]. ERCC6 also regulates chr10 structure by evicting histones flanking DSBs, thereby promoting BRCA1-mediated repair [UniProt references]. ERCC6 mutations cause severe inherited diseases including Cockayne syndrome B and cerebro-oculo-facio-skeletal syndrome, characterized by profound photosensitivity and neurodegeneration 2. CSB-deficient mice and humans show distinct phenotypes due to R-loop formation at neuronal genes abundant in human but not mouse genomes 3. Endogenous formaldehyde-induced transcriptional stress exacerbates disease severity in CSB-deficient models 4. ERCC6 dysfunction is also implicated in age-related macular degeneration, with reduced expression in early AMD retinal epithelium 5, premature ovarian failure 6, and cisplatin resistance in osteosarcoma through PI3K/AKT pathway modulation 7. ERCC6 polymorphisms associate with increased cancer susceptibility 8.