title: DNA Damage-Induced HSPC Malfunction Depends on ROS Accumulation Downstream of IFN-1 Signaling and Bid Mobilization.
abstract: Mouse mutants with an impaired DNA damage response frequently exhibit a set of remarkably similar defects in the HSPC compartment that are of largely unknown molecular basis. Using Mixed-Lineage-Leukemia-5 (Mll5)-deficient mice as prototypical examples, we have identified a mechanistic pathway linking DNA damage and HSPC malfunction. We show that Mll5 deficiency results in accumulation of DNA damage and reactive oxygen species (ROS) in HSPCs. Reduction of ROS efficiently reverses hematopoietic defects, establishing ROS as a major cause of impaired HSPC function. The Ink4a/Arf locus also contributes to HSPC phenotypes, at least in part via promotion of ROS. Strikingly, toxic ROS levels in Mll5-/-mice are critically dependent on type 1 interferon (IFN-1) signaling, which triggers mitochondrial accumulation of full-length Bid. Genetic inactivation of Bid diminishes ROS levels and reverses HSPC defects in Mll5-/-mice. Overall, therefore, our findings highlight an unexpected IFN-1 > Bid > ROS pathway underlying DNA damage-associated HSPC malfunction.
authors.affiliation: Institute of Immunology, University Hospital, 89081 Ulm, Germany; Department of Dermatology, University Hospital, 89081 Ulm, Germany.
authors.forename: Alpaslan
authors.initials: A
authors.lastname: Tasdogan
authors.affiliation: Institute of Immunology, University Hospital, 89081 Ulm, Germany.
authors.forename: Suresh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Institute of Immunology, University Hospital, 89081 Ulm, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Allies
authors.affiliation: Institute of Human Genetics, University Hospital, 89081 Ulm, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bausinger
authors.affiliation: Institute of Immunology, University Hospital, 89081 Ulm, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Beckel
authors.affiliation: Genomics, BioInnovations Zentrum, Technische Universität, 01307 Dresden, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Hofemeister
authors.affiliation: Institute of Experimental Cancer Research, University Clinics, 89081 Ulm, Germany.
authors.forename: Medhanie
authors.initials: M
authors.lastname: Mulaw
authors.affiliation: Institute of Immunology, University Hospital, 89081 Ulm, Germany.
authors.forename: Vikas
authors.initials: V
authors.lastname: Madan
authors.affiliation: Department of Dermatology, University Hospital, 89081 Ulm, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Scharffetter-Kochanek
authors.affiliation: Department of Internal Medicine III, University Hospital, 89081 Ulm, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Feuring-Buske
authors.affiliation: Department of Internal Medicine III, University Hospital, 89081 Ulm, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Doehner
authors.affiliation: Institute of Human Genetics, University Hospital, 89081 Ulm, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Speit
authors.affiliation: Genomics, BioInnovations Zentrum, Technische Universität, 01307 Dresden, Germany.
authors.forename: A Francis
authors.initials: AF
authors.lastname: Stewart
authors.affiliation: Institute of Immunology, University Hospital, 89081 Ulm, Germany. Electronic address: joerg.fehling@uni-ulm.de.
authors.forename: Hans Joerg
authors.initials: HJ
authors.lastname: Fehling
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004249:DNA Damage; D056426:Genetic Loci; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase; D007370:Interferon Type I / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D011070:Poly I-C / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017471:Receptors, Interferon / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D019941:Cyclin-Dependent Kinase Inhibitor p16; D007370:Interferon Type I; D017382:Reactive Oxygen Species; D017471:Receptors, Interferon; D011495:Histone-Lysine N-Methyltransferase; C539231:MLL5 protein, mouse; D011070:Poly I-C; D000111:Acetylcysteine