double-stranded breaks in DNA. Particular pathways of both homologous recombination repair and non-homologous end-joining rely on ERCC1-XPF function. The relevant activity of ERCC1–XPF for both types of double-strand break repair is the ability to remove non-homologous 3′ single-stranded tails from DNA ends before rejoining. This activity is needed during a single-strand annealing subpathway of homologous recombination. Trimming of 3’ single-stranded tail is also needed in a mechanistically distinct subpathway of non-homologous end-joining, dependent on the Ku proteins. Homologous integration of DNA, an important technique for genetic manipulation, is dependent on the function of ERCC1-XPF in the host cell. DNA interstrand crosslink repair Mammalian cells carrying mutations in ERCC1 or XPF are especially sensitive to agents that cause DNA interstrand crosslinks. Interstrand crosslinks block the progression of DNA replication, and structures at blocked DNA replication forks provide substrates for cleavage by ERCC1-XPF. Incisions may be made on either side of the crosslink on one DNA strand to unhook the crosslink and initiate repair. Alternatively, a double-strand break may be made in the DNA near the ICL, and subsequent homologous recombination repair may involve ERCC1-XPF action. Although not the only nuclease involved, ERCC1–XPF is required for ICL repair during several phases of the cell cycle. Clinical significance Cerebro-oculo-facio-skeletal syndrome A few patients with severely disabling ERCC1 mutations that cause cerebro-oculo-facio-skeletal syndrome (COFS) have been reported. COFS syndrome is a rare recessive disorder in which affected individuals undergo rapid neurologic decline and indications of accelerated aging. A very severe case of such disabling mutations is F231L mutation in the tandem helix-hairpin-helix domain of ERCC1 at its interface with XPF. It is shown that this single mutation is very important for the stability of the ERCC1-XPF complex. This Phenylalanine residue is assisting ERCC1 to accommodate a key Phenylalanine residue from XPF (F894) and the mutation (F231L) disturbs this accommodating function. As a consequence, F894 protrudes out of the interface and the mutant complex is dissociating faster compared to the native one. The life span of patients with such mutations is often around 1–2 years. Cockayne syndrome One Cockayne syndrome (CS) type II patient designated CS20LO exhibited a homozygous mutation in exon 7 of ERCC1, producing a F231L mutation. Relevance in chemotherapy Measuring ERCC1 activity may have utility in clinical cancer medicine because one mechanism of resistance to platinum chemotherapy drugs correlates with high ERCC1 activity. Nucleotide excision repair (NER) is the primary DNA repair