ERCC4 (XPF) is the catalytic subunit of the ERCC1-ERCC4 endonuclease complex, which performs structure-specific DNA cleavage essential for genome maintenance 1. The complex nicks DNA at junctions between double-stranded and single-stranded regions, making the 5' incision critical for nucleotide excision repair (NER) and interstrand crosslink (ICL) repair 1. Beyond NER and ICL repair, ERCC1-ERCC4 participates in double-strand break repair via homologous recombination and non-homologous end-joining, base excision repair, and telomere maintenance through interactions with XPA, RPA, SLX4, and TRF2 1. Notably, ERCC4 processes R-loop-derived cytoplasmic RNA-DNA hybrids in an XPF-dependent manner; aberrant R-loop processing activates innate immune responses through cGAS and TLR3 pattern recognition receptors, inducing apoptosis 2. ERCC4 also functions in preventing chromosome 16 by limiting TA-rich DNA cruciform processing 3. Loss-of-function ERCC4 mutations cause severe inherited disorders including xeroderma pigmentosum, Cockayne syndrome, Fanconi anemia complementation group Q, and XFE progeroid syndrome 1. Heterozygous ERCC4 variants associate with increased sunburn susceptibility 4, while common ERCC4 polymorphisms significantly increase cancer risk, particularly for bladder cancer in Asian populations 5.