title: ERCC1 function in nuclear excision and interstrand crosslink repair pathways is mediated exclusively by the ERCC1-202 isoform.
abstract: ERCC1 (excision repair cross-complementation group 1) plays essential roles in the removal of DNA intrastrand crosslinks by nucleotide excision repair, and that of DNA interstrand crosslinks by the Fanconi anemia (FA) pathway and homology-directed repair processes (HDR). The function of ERCC1 thus impacts on the DNA damage response (DDR), particularly in anticancer therapy when DNA damaging agents are employed. ERCC1 expression has been proposed as a predictive biomarker of the response to platinum-based therapy. However, the assessment of ERCC1 expression in clinical samples is complicated by the existence of 4 functionally distinct protein isoforms, which differently impact on DDR. Here, we explored the functional competence of each ERCC1 protein isoform and obtained evidence that the 202 isoform is the sole one endowed with ERCC1 activity in DNA repair pathways. The ERCC1 isoform 202 interacts with RPA, XPA, and XPF, and XPF stability requires expression of the ERCC1 202 isoform (but none of the 3 others). ERCC1-deficient non-small cell lung cancer cells show abnormal mitosis, a phenotype reminiscent of the FA phenotype that can be rescued by isoform 202 only. Finally, we could not observe any dominant-negative interaction between ERCC1 isoforms. These data suggest that the selective assessment of the ERCC1 isoform 202 in clinical samples should accurately reflect the DDR-related activity of the gene and hence constitute a useful biomarker for customizing anticancer therapies.
authors.affiliation: Gustave Roussy; Villejuif, France; INSERM, U981; IRCIV; Villejuif, France; Département Hospitalo-Universitaire Thorax Innovation (DHU TORINO); Villejuif, France; Université Paris Sud; Kremlin-Bicêtre, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Friboulet
authors.forename: Sophie
authors.initials: S
authors.lastname: Postel-Vinay
authors.forename: Tony
authors.initials: T
authors.lastname: Sourisseau
authors.forename: Julien
authors.initials: J
authors.lastname: Adam
authors.forename: Annabelle
authors.initials: A
authors.lastname: Stoclin
authors.forename: Florence
authors.initials: F
authors.lastname: Ponsonnailles
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dorvault
authors.forename: Frédéric
authors.initials: F
authors.lastname: Commo
authors.forename: Patrick
authors.initials: P
authors.lastname: Saulnier
authors.forename: Sophie
authors.initials: S
authors.lastname: Salome-Desmoulez
authors.forename: Géraldine
authors.initials: G
authors.lastname: Pottier
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Ken André
authors.initials: KA
authors.lastname: Olaussen
mesh_terms: D000705:Anaphase / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D048749:Cytokinesis / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D004720:Endonucleases / Q000172:deficiency / Q000378:metabolism*; D005799:Genes, Dominant; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D016685:Mitomycin / Q000494:pharmacology; D011123:Polyploidy; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000172:deficiency / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D020033:Protein Isoforms; C095888:xeroderma pigmentosum group F protein; D016685:Mitomycin; D004247:DNA; C071447:ERCC1 protein, human; D004720:Endonucleases
keywords: DNA repair; ERCC1; NSCLC; interaction; isoform; knock-out; mitosis
references.citation: Nucleic Acids Res. 2012 Nov 1;40(20):9990-10004
references.pmid: 22941649
references.citation: Nucleic Acids Res. 2008 Jan;36(1):1-9
references.pmid: 17962301
references.citation: J Mol Biol. 2011 Oct 21;413(2):337-46
references.pmid: 21875596
references.citation: Int J Mol Med. 1998 Mar;1(3):617-20
references.pmid: 9852275
references.citation: Nat Cell Biol. 2009 Jun;11(6):753-60
references.pmid: 19465922
references.citation: J Clin Invest. 2010 Nov;120(11):3834-42
references.pmid: 20921626
references.citation: DNA Repair (Amst). 2002 Apr 29;1(4):335-40
references.pmid: 12509251
references.citation: Mol Cancer. 2010 Sep 16;9:248
references.pmid: 20846399
references.citation: Nucleic Acids Res. 2009 Oct;37(19):6400-13
references.pmid: 19713438
references.citation: J Biol Chem. 1997 Feb 7;272(6):3833-7
references.pmid: 9013642
references.citation: Cell. 2009 Jul 10;138(1):63-77
references.pmid: 19596235
references.citation: J Biol Chem. 1996 May 10;271(19):11047-50
references.pmid: 8626644
references.citation: Nucleic Acids Res. 1996 Sep 1;24(17):3370-80
references.pmid: 8811092
references.citation: DNA Repair (Amst). 2011 Sep 5;10(9):978-90
references.pmid: 21839691
references.citation: Cancer Res. 2013 Jul 15;73(14):4362-71
references.pmid: 23576554
references.citation: J Biol Chem. 2004 Apr 2;279(14):13634-9
references.pmid: 14734547
references.citation: Mol Cell Biol. 2009 Dec;29(24):6427-37
references.pmid: 19805513
references.citation: Biochemistry. 2010 Jul 6;49(26):5560-9
references.pmid: 20518486
references.citation: N Engl J Med. 2013 Mar 21;368(12):1101-10
references.pmid: 23514287
references.citation: N Engl J Med. 2006 Sep 7;355(10):983-91
references.pmid: 16957145
references.citation: Cell. 1995 Mar 24;80(6):859-68
references.pmid: 7697716
references.citation: Nat Cell Biol. 2013 Aug;15(8):1008-15
references.pmid: 23811686
references.citation: Oncol Rep. 1995 Mar;2(2):209-14
references.pmid: 21597714
references.citation: Mol Cell Biol. 2004 Jul;24(13):5776-87
references.pmid: 15199134
references.citation: Nat Cell Biol. 2009 Jun;11(6):761-8
references.pmid: 19465921
references.citation: DNA Repair (Amst). 2010 Jul 1;9(7):745-53
references.pmid: 20418188
references.citation: Curr Biol. 1997 Jun 1;7(6):427-39
references.pmid: 9197240
references.citation: J Cell Sci. 1998 Feb;111 ( Pt 3):395-404
references.pmid: 9427687
references.citation: Mol Cell. 2009 Jul 10;35(1):116-27
references.pmid: 19595721
references.citation: Genes Cells. 2012 Mar;17(3):173-85
references.pmid: 22353549
references.citation: Cancer Invest. 2009 Nov;27(9):891-7
references.pmid: 19832035
references.citation: Genes Dev. 1998 Aug 15;12(16):2598-609
references.pmid: 9716411
references.citation: Proc Natl Acad Sci U S A. 1994 May 24;91(11):5012-6
references.pmid: 8197174