title: NF-κB-dependent DNA damage-signaling differentially regulates DNA double-strand break repair mechanisms in immature and mature human hematopoietic cells.
abstract: Hematopoietic stem and progenitor cells (HSPC), that is, the cell population giving rise not only to all mature hematopoietic lineages but also the presumed target for leukemic transformation, can transmit (adverse) genetic events, such as are acquired from chemotherapy or ionizing radiation. Data on the repair of DNA double-strand-breaks (DSB) and its accuracy in HSPC are scarce, in part contradictory, and mostly obtained in murine models. We explored the activity, quality and molecular components of DSB repair in human HSPC as compared with mature peripheral blood lymphocytes (PBL). To consider chemotherapy/radiation-induced compensatory proliferation, we established cycling HSPC cultures. Comparison of pathway-specific repair activities using reporter systems revealed that HSPC were severely compromised in non-homologous end joining and homologous recombination but not microhomology-mediated end joining. We observed a more pronounced radiation-induced accumulation of nuclear 53BP1 in HSPC relative to PBL, despite evidence for comparable DSB formation from cytogenetic analysis and γH2AX signal quantification, supporting differential pathway usage. Functional screening excluded a major influence of phosphatidylinositol-3-OH-kinase (ATM/ATR/DNA-PK)- and p53-signaling as well as chromatin remodeling. We identified diminished NF-κB signaling as the molecular component underlying the observed differences between HSPC and PBL, limiting the expression of DSB repair genes and bearing the risk of an inaccurate repair.
authors: Department of Biophysics, GSI Helmholtz Center for Heavy Ion Research, Planckstrasse, Darmstadt, Germany.
authors: D
authors: D
authors: Kraft
authors: Department of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse, Ulm, Germany.
authors: M
authors: M
authors: Rall
authors: Department of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse, Ulm, Germany.
authors: M
authors: M
authors: Volcic
authors: Department of Biophysics, GSI Helmholtz Center for Heavy Ion Research, Planckstrasse, Darmstadt, Germany.
authors: E
authors: E
authors: Metzler
authors: Department of Biophysics, GSI Helmholtz Center for Heavy Ion Research, Planckstrasse, Darmstadt, Germany.
authors: A
authors: A
authors: Groo
authors: Department of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse, Ulm, Germany.
authors: A
authors: A
authors: Stahl
authors: Department of Biophysics, GSI Helmholtz Center for Heavy Ion Research, Planckstrasse, Darmstadt, Germany.
authors: L
authors: L
authors: Bauer
authors: Department of Biophysics, GSI Helmholtz Center for Heavy Ion Research, Planckstrasse, Darmstadt, Germany.
authors: E
authors: E
authors: Nasonova
authors: Department of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse, Ulm, Germany.
authors: D
authors: D
authors: Salles
authors: Department of Biophysics, GSI Helmholtz Center for Heavy Ion Research, Planckstrasse, Darmstadt, Germany.
authors: G
authors: G
authors: Taucher-Scholz
authors: Department of Cellular Therapeutics/Cell Processing, DRK-Blutspendedienst Baden-Württemberg - Hessen, Sandhofstrasse, Frankfurt, Germany.
authors: H
authors: H
authors: Bönig
authors: Department of Biophysics, GSI Helmholtz Center for Heavy Ion Research, Planckstrasse, Darmstadt, Germany.
authors: C
authors: C
authors: Fournier
authors: Department of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse, Ulm, Germany.
authors: L
authors: L
authors: Wiesmüller
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; D016328:NF-kappa B
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