ERCC1

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Excision repair cross-complementation group 1
Protein ERCC1 PDB 1z00.png
PDB rendering based on 1z00.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ERCC1 ; COFS4; RAD10; UV20
External IDs OMIM126380 MGI95412 HomoloGene1501 GeneCards: ERCC1 Gene
RNA expression pattern
PBB GE ERCC1 203720 s at tn.png
PBB GE ERCC1 203719 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2067 13870
Ensembl ENSG00000012061 ENSMUSG00000003549
UniProt P07992 P07903
RefSeq (mRNA) NM_001166049 NM_001127324
RefSeq (protein) NP_001159521 NP_001120796
Location (UCSC) Chr 19:
45.91 – 45.98 Mb
Chr 7:
19.34 – 19.36 Mb
PubMed search [1] [2]

DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ERCC1 gene.[1]

Function[edit]

The function of the ERCC1 protein is predominantly in nucleotide excision repair (NER) of damaged DNA. NER is one of five separate DNA repair mechanisms that also include recombination repair, base excision repair, mismatch repair, and translesion synthesis.

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.[citation needed] ERCC1 has a role in homology-dependent gene targeting events.[citation needed] In telomere maintenance, XPF/ERCC1 degrades 3′ G-rich overhangs [2] and may have other functions. [3]

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.[citation needed]

Clinical significance[edit]

Mutations in the human ERCC1 gene result in cerebrooculofacioskeletal syndrome[4][5] and polymorphisms that alter expression of this gene may play a role in carcinogenesis.[6]

Relevance in chemotherapy[edit]

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,[7] ovarian, colorectal and bladder cancers.[8] 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.[9][10]

ERCC1 genotyping in humans has shown significant polymorphism at codon 118.[citation needed] These polymorphisms may have differential effects on platinum and mitomycin damage.[citation needed]

References[edit]

  1. ^ 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". Nature 310 (5976): 425–9. doi:10.1038/310425a0. PMID 6462228. 
  2. ^ 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. PMID 20944091. 
  3. ^ Rahn JJ, Adair GM, Nairn RS (July 2010). "Multiple roles of ERCC1-XPF in mammalian interstrand crosslink repair". Environ. Mol. Mutagen. 51 (6): 567–81. doi:10.1002/em.20583. PMID 20658648. 
  4. ^ Suzumura H, Arisaka O (2010). Cerebro-Oculo-Facio-Skeletal Syndrome. "Cerebro-oculo-facio-skeletal syndrome.". Adv Exp Med Biol. Advances in Experimental Medicine and Biology 685: 210–4. doi:10.1007/978-1-4419-6448-9_19. ISBN 978-1-4419-6447-2. PMID 20687508. 
  5. ^ >Jaspers, N. G. J., Raams, A., Silengo, M. C., Wijgers, N., Niedernhofer, L. J., Robinson, A. R., Giglia-Mari, G., Hoogstraten, D., Kleijer, W. J., Hoeijmakers, J. H. J., Vermeulen, W. (2007). "First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure". Am. J. Hum. Genet. 80 (3): 457–466, 2007. doi:10.1086/512486. PMC 1821117. PMID 17273966. 
  6. ^ Goode EL, Ulrich CM, Potter JD (2002). "Polymorphisms in DNA repair genes and associations with cancer risk". Cancer Epidemiol Biomarkers Prev 11 (12): 1513–30. PMID 12496039. 
  7. ^ 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 Oncol 18 (3): 504–9. doi:10.1093/annonc/mdl430. PMID 17322540. 
  8. ^ 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 Oncol 18 (3): 522–8. doi:10.1093/annonc/mdl435. PMID 17229776. 
  9. ^ 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 Med 355 (10): 983–91. doi:10.1056/NEJMoa060570. PMID 16957145. 
  10. ^ Soria JC (2007). "ERCC1-tailored chemotherapy in lung cancer: the first prospective randomized trial". J Clin Oncol 25 (19): 2648–9. doi:10.1200/JCO.2007.11.3167. PMID 17602070. 

Further reading[edit]

External links[edit]