title: ATR-mediated phosphorylation of FANCI regulates dormant origin firing in response to replication stress.
abstract: Excess dormant origins bound by the minichromosome maintenance (MCM) replicative helicase complex play a critical role in preventing replication stress, chromosome instability, and tumorigenesis. In response to DNA damage, replicating cells must coordinate DNA repair and dormant origin firing to ensure complete and timely replication of the genome; how cells regulate this process remains elusive. Herein, we identify a member of the Fanconi anemia (FA) DNA repair pathway, FANCI, as a key effector of dormant origin firing in response to replication stress. Cells lacking FANCI have reduced number of origins, increased inter-origin distances, and slowed proliferation rates. Intriguingly, ATR-mediated FANCI phosphorylation inhibits dormant origin firing while promoting replication fork restart/DNA repair. Using super-resolution microscopy, we show that FANCI co-localizes with MCM-bound chromatin in response to replication stress. These data reveal a unique role for FANCI as a modulator of dormant origin firing and link timely genome replication to DNA repair.
authors.affiliation: Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Yu-Hung
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA; Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Mathew J K
authors.initials: MJ
authors.lastname: Jones
authors.affiliation: Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Yandong
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Crist
authors.affiliation: Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Colnaghi
authors.affiliation: Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sims
authors.affiliation: Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Rothenberg
authors.affiliation: Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Prasad V
authors.initials: PV
authors.lastname: Jallepalli
authors.affiliation: Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA. Electronic address: tony.huang@nyumc.org.
authors.forename: Tony T
authors.initials: TT
authors.lastname: Huang
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism*; D004249:DNA Damage; D004261:DNA Replication; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D064110:Minichromosome Maintenance Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; C519921:FANCI protein, human; D051856:Fanconi Anemia Complementation Group Proteins; C068619:CDC7 protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D064110:Minichromosome Maintenance Proteins; D006918:Hydroxyurea
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