title: XPF-ERCC1 acts in Unhooking DNA interstrand crosslinks in cooperation with FANCD2 and FANCP/SLX4.
abstract: DNA interstrand crosslinks (ICLs), highly toxic lesions that covalently link the Watson and Crick strands of the double helix, are repaired by a complex, replication-coupled pathway in higher eukaryotes. The earliest DNA processing event in ICL repair is the incision of parental DNA on either side of the ICL ("unhooking"), which allows lesion bypass. Incisions depend critically on the Fanconi anemia pathway, whose activation involves ubiquitylation of the FANCD2 protein. Using Xenopus egg extracts, which support replication-coupled ICL repair, we show that the 3' flap endonuclease XPF-ERCC1 cooperates with SLX4/FANCP to carry out the unhooking incisions. Efficient recruitment of XPF-ERCC1 and SLX4 to the ICL depends on FANCD2 and its ubiquitylation. These data help define the molecular mechanism by which the Fanconi anemia pathway promotes a key event in replication-coupled ICL repair.
authors.affiliation: Hubrecht Institute-KNAW, University Medical Center Utrecht and Cancer Genomics Netherlands, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Daisy
authors.initials: D
authors.lastname: Klein Douwel
authors.affiliation: Hubrecht Institute-KNAW, University Medical Center Utrecht and Cancer Genomics Netherlands, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Rick A C M
authors.initials: RA
authors.lastname: Boonen
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Long
authors.affiliation: Hubrecht Institute-KNAW, University Medical Center Utrecht and Cancer Genomics Netherlands, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Szypowska
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Räschle
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Walter
authors.affiliation: Hubrecht Institute-KNAW, University Medical Center Utrecht and Cancer Genomics Netherlands, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands. Electronic address: p.knipscheer@hubrecht.eu.
authors.forename: Puck
authors.initials: P
authors.lastname: Knipscheer
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D053837:DNA Cleavage; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004706:Endodeoxyribonucleases; D004720:Endonucleases / Q000737:chemistry / Q000378:metabolism*; D005090:Exodeoxyribonucleases / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D064251:Multifunctional Enzymes; D011485:Protein Binding; D045522:Recombinases / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination; D029867:Xenopus Proteins / Q000737:chemistry / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D004268:DNA-Binding Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D064251:Multifunctional Enzymes; D045522:Recombinases; D029867:Xenopus Proteins; C095888:xeroderma pigmentosum group F protein; C071447:ERCC1 protein, human; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D005090:Exodeoxyribonucleases; C551063:FAN1 protein, human; C498772:MUS81 protein, human; C542319:SLX4 protein, human
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