title: FANCD2 and CtIP cooperate to repair DNA interstrand crosslinks.
abstract: The resolution of DNA interstrand crosslinks (ICLs) requires a complex interplay between several processes of DNA metabolism, including the Fanconi anemia (FA) pathway and homologous recombination (HR). FANCD2 monoubiquitination and CtIP-dependent DNA-end resection represent key events in FA and HR activation, respectively, but very little is known about their functional relationship. Here, we show that CtIP physically interacts with both FANCD2 and ubiquitin and that monoubiquitinated FANCD2 tethers CtIP to damaged chromatin, which helps channel DNA double-strand breaks generated during ICL processing into the HR pathway. Consequently, CtIP mutants defective in FANCD2 binding fail to associate with damaged chromatin, which leads to increased levels of nonhomologous end-joining activity and ICL hypersensitivity. Interestingly, we also observe that CtIP depletion aggravates the genomic instability in FANCD2-deficient cells. Thus, our data indicate that FANCD2 primes CtIP-dependent resection during HR after ICL induction but that CtIP helps prevent illegitimate recombination in FA cells.
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Olga
authors.initials: O
authors.lastname: Murina
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: von Aesch
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Ufuk
authors.initials: U
authors.lastname: Karakus
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Lorenza P
authors.initials: LP
authors.lastname: Ferretti
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Hella A
authors.initials: HA
authors.lastname: Bolck
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Kay
authors.initials: K
authors.lastname: Hänggi
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland. Electronic address: sartori@imcr.uzh.ch.
authors.forename: Alessandro A
authors.initials: AA
authors.lastname: Sartori
mesh_terms: D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D053837:DNA Cleavage; D004260:DNA Repair; D004706:Endodeoxyribonucleases; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D009687:Nuclear Proteins; D025801:Ubiquitin; D004247:DNA; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human