The DNA Damage Response Regulates RAG1/2 Expression in Pre–B Cells through ATM-FOXO1 Signaling

Autor: Jeroen E. J. Guikema, Timon A. Bloedjes, Carel J. M. van Noesel, Carol E. Schrader, Katarina Ochodnicka-Mackovicova, Richard J. Bende, Amélie van der Veen, Alexander M. de Bruin, Rudi W. Hendriks, Mahnoush Bahjat, Harmen van Andel, Chiel Maas, Els Verhoeyen
Přispěvatelé: Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Pulmonary Medicine, Graduate School, Pathology, Other departments, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam
Rok vydání: 2016
Předmět:
0301 basic medicine
Precursor Cells
DNA damage
Cells
Immunology
chemical and pharmacologic phenomena
Ataxia Telangiectasia Mutated Proteins
Genotoxic Stress
Biology
Recombination-activating gene
03 medical and health sciences
0302 clinical medicine
RAG2
Humans
Immunology and Allergy
Enhancer
Cells
Cultured
B-Lymphoid
Homeodomain Proteins
Cultured
Forkhead Box Protein O1
Precursor Cells
B-Lymphoid
HEK 293 cells
T-cell receptor
Nuclear Proteins
hemic and immune systems
[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Molecular biology
DNA-Binding Proteins
HEK293 Cells
030104 developmental biology
[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology
[SDV.IMM]Life Sciences [q-bio]/Immunology
Signal transduction
DNA Damage
Signal Transduction
030215 immunology
Zdroj: Journal of Immunology (Baltimore, Md.: 1950)
Journal of Immunology (Baltimore, Md.: 1950), 2016, 197 (7), pp.2918-2929. ⟨10.4049/jimmunol.1501989⟩
Journal of Immunology, 197(7), 2918-2929. American Association of Immunologists
Journal of immunology (Baltimore, Md., 197(7), 2918-2929. American Association of Immunologists
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.1501989
Popis: The recombination activating gene (RAG) 1 and RAG2 protein complex introduces DNA breaks at Tcr and Ig gene segments that are required for V(D)J recombination in developing lymphocytes. Proper regulation of RAG1/2 expression safeguards the ordered assembly of Ag receptors and the development of lymphocytes, while minimizing the risk for collateral damage. The ataxia telangiectasia mutated (ATM) kinase is involved in the repair of RAG1/2-mediated DNA breaks and prevents their propagation. The simultaneous occurrence of RAG1/2-dependent and -independent DNA breaks in developing lymphocytes exposed to genotoxic stress increases the risk for aberrant recombinations. In this study, we assessed the effect of genotoxic stress on RAG1/2 expression in pre–B cells and show that activation of the DNA damage response resulted in the rapid ATM-dependent downregulation of RAG1/2 mRNA and protein expression. We show that DNA damage led to the loss of FOXO1 binding to the enhancer region of the RAG1/2 locus (Erag) and provoked FOXO1 cleavage. We also show that DNA damage caused by RAG1/2 activity in pre–B cells was able to downmodulate RAG1/2 expression and activity, confirming the existence of a negative feedback regulatory mechanism. Our data suggest that pre–B cells are endowed with a protective mechanism that reduces the risk for aberrant recombinations and chromosomal translocations when exposed to DNA damage, involving the ATM-dependent regulation of FOXO1 binding to the Erag enhancer region.
Databáze: OpenAIRE
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