title: mTOR regulates DNA damage response through NF-κB-mediated FANCD2 pathway in hematopoietic cells.
abstract: Hematopoietic stem/progenitor cells (HSPCs) function to give rise to mature blood cells. Effective DNA damage response (DDR) and maintenance of genomic stability are crucial for normal functioning of HSPCs. Mammalian target of rapamycin (mTOR) integrates signals from nutrients and growth factors to control protein synthesis, cell growth, survival and metabolism, and has been shown to regulate DDR in yeast and human cancer cells through the p53/p21 signaling cascade. Here, we show that gene targeting of mTOR in HSPCs causes a defective DDR due to a variety of DNA damage agents, mimicking that caused by deficient FANCD2, a key component of the Fanconi anemia (FA) DDR machinery. Mechanistically, mTOR(-/-) HSPCs express drastically reduced FANCD2. Consistent with these genetic findings, inactivation of mTOR in human lymphoblast cells by pp242 or Torin 1, mTOR kinase inhibitors, suppresses FANCD2 expression and causes a defective DDR that can be rescued by reconstitution of exogenous FANCD2. Further mechanistic studies show that mTOR deficiency or inactivation increases phosphorylation and nuclear translocation of nuclear factor (NF)-κB, which results in an enhanced NF-κB binding to FANCD2 promoter to suppress FANCD2 expression. Thus, mTOR regulates DDR and genomic stability in hematopoietic cells through a noncanonical pathway involving NF-κB-mediated FANCD2 expression.
authors.affiliation: Department of Biotechnology, Jinan University, Guangzhou, Guangdong, China.|Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: F
authors.initials: F
authors.lastname: Guo
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: W
authors.initials: W
authors.lastname: Du
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: O'Connor
authors.affiliation: Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: G
authors.initials: G
authors.lastname: Thomas
authors.affiliation: Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kozma
authors.affiliation: Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: B
authors.initials: B
authors.lastname: Zingarelli
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Pang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D019457:Chromosome Breakage; D020552:Comet Assay; D004249:DNA Damage; D024202:Electrophoretic Mobility Shift Assay; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D042822:Genomic Instability; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009287:Naphthyridines / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D052236:Fanconi Anemia Complementation Group D2 Protein; D016328:NF-kappa B; D009287:Naphthyridines; D010446:Peptide Fragments; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
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