title: FANCD2 binds MCM proteins and controls replisome function upon activation of s phase checkpoint signaling.
abstract: Proteins disabled in Fanconi anemia (FA) are necessary for the maintenance of genome stability during cell proliferation. Upon replication stress signaling by ATR, the FA core complex monoubiquitinates FANCD2 and FANCI in order to activate DNA repair. Here, we identified FANCD2 and FANCI in a proteomic screen of replisome-associated factors bound to nascent DNA in response to replication arrest. We found that FANCD2 can interact directly with minichromosome maintenance (MCM) proteins. ATR signaling promoted the transient association of endogenous FANCD2 with the MCM2-MCM7 replicative helicase independently of FANCD2 monoubiquitination. FANCD2 was necessary for human primary cells to restrain DNA synthesis in the presence of a reduced pool of nucleotides and prevented the accumulation of single-stranded DNA, the induction of p21, and the entry of cells into senescence. These data reveal that FANCD2 is an effector of ATR signaling implicated in a general replisome surveillance mechanism that is necessary for sustaining cell proliferation and attenuating carcinogenesis.
authors.affiliation: Institute of Human Genetics, UPR 1142, CNRS, 141, rue de la Cardonille, 34396 Montpellier, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Lossaint
authors.forename: Marion
authors.initials: M
authors.lastname: Larroque
authors.forename: Cyril
authors.initials: C
authors.lastname: Ribeyre
authors.forename: Nicole
authors.initials: N
authors.lastname: Bec
authors.forename: Christian
authors.initials: C
authors.lastname: Larroque
authors.forename: Chantal
authors.initials: C
authors.lastname: Décaillet
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gari
authors.forename: Angelos
authors.initials: A
authors.lastname: Constantinou
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D004261:DNA Replication; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D006801:Humans; D064111:Minichromosome Maintenance Complex Component 2 / Q000235:genetics / Q000378:metabolism*; D064168:Minichromosome Maintenance Complex Component 7 / Q000235:genetics / Q000378:metabolism*; D059807:S Phase Cell Cycle Checkpoints / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics
chemical_list: C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C084859:MCM2 protein, human; C101624:MCM7 protein, human; D064111:Minichromosome Maintenance Complex Component 2; D064168:Minichromosome Maintenance Complex Component 7