title: FANCI Regulates Recruitment of the FA Core Complex at Sites of DNA Damage Independently of FANCD2.
abstract: The Fanconi anemia (FA)-BRCA pathway mediates repair of DNA interstrand crosslinks. The FA core complex, a multi-subunit ubiquitin ligase, participates in the detection of DNA lesions and monoubiquitinates two downstream FA proteins, FANCD2 and FANCI (or the ID complex). However, the regulation of the FA core complex itself is poorly understood. Here we show that the FA core complex proteins are recruited to sites of DNA damage and form nuclear foci in S and G2 phases of the cell cycle. ATR kinase activity, an intact FA core complex and FANCM-FAAP24 were crucial for this recruitment. Surprisingly, FANCI, but not its partner FANCD2, was needed for efficient FA core complex foci formation. Monoubiquitination or ATR-dependent phosphorylation of FANCI were not required for the FA core complex recruitment, but FANCI deubiquitination by USP1 was. Additionally, BRCA1 was required for efficient FA core complex foci formation. These findings indicate that FANCI functions upstream of FA core complex recruitment independently of FANCD2, and alter the current view of the FA-BRCA pathway.
authors.affiliation: Howard Hughes Medical Institute, Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Castella
authors.affiliation: Howard Hughes Medical Institute, Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Celine
authors.initials: C
authors.lastname: Jacquemont
authors.affiliation: Biochemistry, Molecular Biology, and Biophysics Department, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Thompson
authors.affiliation: Biochemistry, Molecular Biology, and Biophysics Department, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Yeo
authors.affiliation: Howard Hughes Medical Institute, Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Cheung
authors.affiliation: Howard Hughes Medical Institute, Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Jen-Wei
authors.initials: JW
authors.lastname: Huang
authors.affiliation: Biochemistry, Molecular Biology, and Biophysics Department, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sobeck
authors.affiliation: Biochemistry, Molecular Biology, and Biophysics Department, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hendrickson
authors.affiliation: Howard Hughes Medical Institute, Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Taniguchi
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D001853:Bone Marrow / Q000473:pathology; D002843:Chromatin / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D005199:Fanconi Anemia / Q000235:genetics* / Q000473:pathology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D045325:HCT116 Cells; D006801:Humans; D010766:Phosphorylation; D034741:RNA, Small Interfering; D015398:Signal Transduction; D054875:Ubiquitination / Q000235:genetics
chemical_list: D002843:Chromatin; C519921:FANCI protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D034741:RNA, Small Interfering; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins