DNA damage-induced p53 downregulates expression of RAG1 through a negative feedback loop involving miR-34a and FOXP1.

Autor:	Ochodnicka-Mackovicova K; Department of Pathology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands., van Keimpema M; Department of Pathology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands., Spaargaren M; Department of Pathology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands; Cancer Center Amsterdam (CCA), Cancer Biology and Immunology - Target & Therapy Discovery, Amsterdam, The Netherlands., van Noesel CJM; Department of Pathology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands., Guikema JEJ; Department of Pathology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands. Electronic address: J.E.Guikema@amsterdamumc.nl.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2024 Oct 23; Vol. 300 (12), pp. 107922. Date of Electronic Publication: 2024 Oct 23.
DOI:	10.1016/j.jbc.2024.107922
Abstrakt:	During the maturation of pre-B cells, the recombination activating gene 1 and 2 (RAG1/2) endonuclease complex plays a crucial role in coordinating V(D)J recombination by introducing DNA breaks in immunoglobulin (Ig) loci. Dysregulation of RAG1/2 has been linked to the onset of B cell malignancies, yet the mechanisms controlling RAG1/2 in pre-B cells exposed to excessive DNA damage are not fully understood. In this study, we show that DNA damage-induced activation of p53 initiates a negative-feedback loop which rapidly downregulates RAG1 levels. This feedback loop involves ataxia telangiectasia mutated activation, subsequent stabilization of p53, and modulation of microRNA-34a (miR-34a) levels, which is one of the p53 targets. Notably, this loop incorporates transcription factor forkhead box P1 as a downstream effector. The absence of p53 resulted in an increased proportion of IgM + cells prompted to upregulate RAG1/2 and to undergo Ig light chain recombination. Similar results were obtained in primary pre-B cells with depleted levels of miR-34a. We propose that in pre-B cells undergoing Ig gene recombination, the DNA breaks activate a p53/miR-34a/forkhead box P1-mediated negative-feedback loop that contributes to the rapid downregulation of RAG. This regulation limits the RAG-dependent DNA damage, thereby protecting the stability of the genome during V(D)J rearrangement in developing B cells. Competing Interests: Conflict of interest The authors declare no conflict of interest with the contents of this article. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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