title: UHRF1 is a sensor for DNA interstrand crosslinks and recruits FANCD2 to initiate the Fanconi anemia pathway.
abstract: The Fanconi anemia (FA) pathway is critical for the cellular response to toxic DNA interstrand crosslinks (ICLs). Using a biochemical purification strategy, we identified UHRF1 as a protein that specifically interacts with ICLs in vitro and in vivo. Reduction of cellular levels of UHRF1 by RNAi attenuates the FA pathway and sensitizes cells to mitomycin C. Knockdown cells display a drastic reduction in FANCD2 foci formation. Using live-cell imaging, we observe that UHRF1 is rapidly recruited to chromatin in response to DNA crosslinking agents and that this recruitment both precedes and is required for the recruitment of FANCD2 to ICLs. Based on these results, we describe a mechanism of ICL sensing and propose that UHRF1 is a critical factor that binds to ICLs. In turn, this binding is necessary for the subsequent recruitment of FANCD2, which allows the DNA repair process to initiate.
authors: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors: Chih-Chao
authors: CC
authors: Liang
authors: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors: Bao
authors: B
authors: Zhan
authors: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors: Yasunaga
authors: Y
authors: Yoshikawa
authors: Department of Cell Biology, Harvard Medical School, Boston, MA 01125, USA.
authors: Wilhelm
authors: W
authors: Haas
authors: Department of Cell Biology, Harvard Medical School, Boston, MA 01125, USA.
authors: Steven P
authors: SP
authors: Gygi
authors: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK. Electronic address: martin.cohn@bioch.ox.ac.uk.
authors: Martin A
authors: MA
authors: Cohn
mesh_terms: D000595:Amino Acid Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000235:genetics; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology; D005199:Fanconi Anemia / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D002843:Chromatin; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D004247:DNA; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases