title: The FANCD2-FANCI complex is recruited to DNA interstrand crosslinks before monoubiquitination of FANCD2.
abstract: The Fanconi anaemia (FA) pathway is important for the repair of DNA interstrand crosslinks (ICL). The FANCD2-FANCI complex is central to the pathway, and localizes to ICLs dependent on its monoubiquitination. It has remained elusive whether the complex is recruited before or after the critical monoubiquitination. Here, we report the first structural insight into the human FANCD2-FANCI complex by obtaining the cryo-EM structure. The complex contains an inner cavity, large enough to accommodate a double-stranded DNA helix, as well as a protruding Tower domain. Disease-causing mutations in the Tower domain are observed in several FA patients. Our work reveals that recruitment of the complex to a stalled replication fork serves as the trigger for the activating monoubiquitination event. Taken together, our results uncover the mechanism of how the FANCD2-FANCI complex activates the FA pathway, and explains the underlying molecular defect in FA patients with mutations in the Tower domain.
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: Chih-Chao
authors.initials: CC
authors.lastname: Liang
authors.affiliation: Institute of Mineralogy, Materials Physics and Cosmochemistry, UMR 7590, UPMC, CNRS, IRD, MNHN, Paris F-75005, France.
authors.forename: Zhuolun
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: David
authors.initials: D
authors.lastname: Lopez-Martinez
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: William V
authors.identifier: 0000-0001-6614-0194
authors.initials: WV
authors.lastname: Nicholson
authors.affiliation: Institute of Mineralogy, Materials Physics and Cosmochemistry, UMR 7590, UPMC, CNRS, IRD, MNHN, Paris F-75005, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vénien-Bryan
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Cohn
mesh_terms: D020285:Cryoelectron Microscopy; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D024202:Electrophoretic Mobility Shift Assay; D005199:Fanconi Anemia / Q000235:genetics*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure*; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure*; D006801:Humans; D000072417:Protein Domains / Q000235:genetics; D054875:Ubiquitination
chemical_list: C499905:FANCD2 protein, human; C519921:FANCI protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D004247:DNA