Nucleotide excision repair in eukaryotes is initiated by either Global Genome NER(GG-NER) or Transcription Coupled NER(TC-NER) which involve distinct protein complexes, each recognizing damaged DNA. Thereafter, subsequent steps in GG-NER and TC-NER share a final common excision and repair pathway. Transcription factor II H (TFIIH) separates the abnormal strand from the normal strand. Xeroderma pigmentosum group G (XPG) cuts 3’ to the damaged DNA. Replication protein A (RPA) protects the normal strand. Xeroderma pigmentosum group A (XPA) isolates the damaged segment on the strand to be cut. ERCC1 and xeroderma pigmentosum group F (XPF) cut 5' to the damaged DNA. ERCC1 appears to have a crucial role in stabilizing and enhancing the functionality of the XPF endonuclease. The excised single-stranded DNA of approximately 30 nucleotides and attached NER proteins are removed. DNA polymerases and ligases fill in the gap using the normal strand as a template.
In mammals, the XPF/ERCC1 protein complex also removes nonhomologous 3′ tail ends in homologous recombination. ERCC1 has a role in homology-dependent gene targeting events. In telomere maintenance, XPF/ERCC1 degrades 3′ G-rich overhangs  and may have other functions. 
ERCC1 knockout mice are runted at birth and die from progressive hepatic insufficiency. Liver failure also occurs in XPF knockout mice, but not mice deficient in any other nucleotide excision repair protein.
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 mechanism that removes the therapeutic platinum-DNA adducts from the tumor DNA. ERCC1 activity levels, being an important part of the NER common final pathway, may serve as a marker of general NER throughput. This has been suggested for patients with gastric, ovarian, colorectal and bladder cancers. In Non-small cell lung carcinoma (NSCLC), surgically removed tumors that receive no further therapy have a better survival if ERCC1-positive than if ERCC1-negative. Thus ERCC1 positivity is a favorable prognostic marker, referring to how the disease will proceed if not further treated. ERCC1-positive NSCLC tumors do not benefit from adjuvant platinum chemotherapy. However, ERCC1-negative NSCLC tumors, prognostically worse without treatment, derive substantial benefit from adjuvant cisplatin-based chemotherapy. High ERCC1 is thus a negative predictive marker, referring to how it will respond to a specific type of treatment.
ERCC1 genotyping in humans has shown significant polymorphism at codon 118. These polymorphisms may have differential effects on platinum and mitomycin damage.
^Westerveld A, Hoeijmakers JH, van Duin M, de Wit J, Odijk H, Pastink A, Wood RD, Bootsma D (Sep 1984). "Molecular cloning of a human DNA repair gene". Nature310 (5976): 425–9. doi:10.1038/310425a0. PMID6462228.
^Kirschner K, Melton DW (September 2010). "Multiple roles of the ERCC1-XPF endonuclease in DNA repair and resistance to anticancer drugs". Anticancer Res.30 (9): 3223–32. PMID20944091.
^Goode EL, Ulrich CM, Potter JD (2002). "Polymorphisms in DNA repair genes and associations with cancer risk". Cancer Epidemiol Biomarkers Prev11 (12): 1513–30. PMID12496039.
^Kwon HC, Roh MS, Oh SY, Kim SH, Kim MC, Kim JS et al. (2007). "Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer". Ann Oncol18 (3): 504–9. doi:10.1093/annonc/mdl430. PMID17322540.
^Bellmunt J, Paz-Ares L, Cuello M, Cecere FL, Albiol S, Guillem V et al. (2007). "Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy". Ann Oncol18 (3): 522–8. doi:10.1093/annonc/mdl435. PMID17229776.
^Olaussen KA, Dunant A, Fouret P, Brambilla E, André F, Haddad V et al. (2006). "DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy". N Engl J Med355 (10): 983–91. doi:10.1056/NEJMoa060570. PMID16957145.
Olaussen KA, Mountzios G, Soria JC (2007). "ERCC1 as a risk stratifier in platinum-based chemotherapy for nonsmall-cell lung cancer". Current Opinion in Pulmonary Medicine13 (4): 284–9. doi:10.1097/MCP.0b013e32816b5c63. PMID17534174.
van Duin M, de Wit J, Odijk H, et al. (1986). "Molecular characterization of the human excision repair gene ERCC-1: cDNA cloning and amino acid homology with the yeast DNA repair gene RAD10". Cell44 (6): 913–23. doi:10.1016/0092-8674(86)90014-0. PMID2420469.
Hoeijmakers JH (1987). "Characterization of genes and proteins involved in excision repair of human cells". J. Cell Sci. Suppl.6: 111–25. PMID2821019.
Hoeijmakers JH, van Duin M, Westerveld A, et al. (1987). "Identification of DNA repair genes in the human genome". Cold Spring Harb. Symp. Quant. Biol.51 (1): 91–101. doi:10.1101/sqb.1986.051.01.012. PMID3034490.
Nagai A, Saijo M, Kuraoka I, et al. (1995). "Enhancement of damage-specific DNA binding of XPA by interaction with the ERCC1 DNA repair protein". Biochem. Biophys. Res. Commun.211 (3): 960–6. doi:10.1006/bbrc.1995.1905. PMID7598728.
McWhir J, Selfridge J, Harrison DJ, et al. (1994). "Mice with DNA repair gene (ERCC-1) deficiency have elevated levels of p53, liver nuclear abnormalities and die before weaning". Nat. Genet.5 (3): 217–24. doi:10.1038/ng1193-217. PMID8275084.
Trask B, Fertitta A, Christensen M, et al. (1993). "Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers". Genomics15 (1): 133–45. doi:10.1006/geno.1993.1021. PMID8432525.
Cheng L, Guan Y, Li L, et al. (1999). "Expression in normal human tissues of five nucleotide excision repair genes measured simultaneously by multiplex reverse transcription-polymerase chain reaction". Cancer Epidemiol. Biomarkers Prev.8 (9): 801–7. PMID10498399.
Yu JJ, Thornton K, Guo Y, et al. (2002). "An ERCC1 splicing variant involving the 5'-UTR of the mRNA may have a transcriptional modulatory function". Oncogene20 (52): 7694–8. doi:10.1038/sj.onc.1204977. PMID11753647.
Li QQ, Yunmbam MK, Zhong X, et al. (2002). "Lactacystin enhances cisplatin sensitivity in resistant human ovarian cancer cell lines via inhibition of DNA repair and ERCC-1 expression". Cell. Mol. Biol. (Noisy-le-grand). 47 Online Pub: OL61–72. PMID11936875.