Loss of full-length hnRNP R isoform impairs DNA damage response in motoneurons by inhibiting Yb1 recruitment to chromatin
Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-265687
- Neurons critically rely on the functions of RNA-binding proteins to maintain their polarity and resistance to neurotoxic stress. HnRNP R has a diverse range of post-transcriptional regulatory functions and is important for neuronal development by regulating axon growth. Hnrnpr pre-mRNA undergoes alternative splicing giving rise to a full-length protein and a shorter isoform lacking its N-terminal acidic domain. To investigate functions selectively associated with the full-length hnRNP R isoform, we generated a Hnrnpr knockout mouseNeurons critically rely on the functions of RNA-binding proteins to maintain their polarity and resistance to neurotoxic stress. HnRNP R has a diverse range of post-transcriptional regulatory functions and is important for neuronal development by regulating axon growth. Hnrnpr pre-mRNA undergoes alternative splicing giving rise to a full-length protein and a shorter isoform lacking its N-terminal acidic domain. To investigate functions selectively associated with the full-length hnRNP R isoform, we generated a Hnrnpr knockout mouse (Hnrnpr\(^{tm1a/tm1a}\)) in which expression of full-length hnRNP R was abolished while production of the truncated hnRNP R isoform was retained. Motoneurons cultured from Hnrnpr\(^{tm1a/tm1a}\) mice did not show any axonal growth defects but exhibited enhanced accumulation of double-strand breaks and an impaired DNA damage response upon exposure to genotoxic agents. Proteomic analysis of the hnRNP R interactome revealed the multifunctional protein Yb1 as a top interactor. Yb1-depleted motoneurons were defective in DNA damage repair. We show that Yb1 is recruited to chromatin upon DNA damage where it interacts with gamma-H2AX, a mechanism that is dependent on full-length hnRNP R. Our findings thus suggest a novel role of hnRNP R in maintaining genomic integrity and highlight the function of its N-terminal acidic domain in this context.…
Autor(en): | Hanaa Ghanawi, Luisa Hennlein, Abdolhossein Zare, Jakob Bader, Saeede Salehi, Daniel Hornburg, Changhe Ji, Rajeeve Sivadasan, Carsten Drepper, Felix Meissner, Matthias Mann, Sibylle Jablonka, Michael Briese, Michael SendtnerORCiD |
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URN: | urn:nbn:de:bvb:20-opus-265687 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Medizinische Fakultät / Institut für Klinische Neurobiologie |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | Nucleic Acids Research |
Erscheinungsjahr: | 2021 |
Band / Jahrgang: | 49 |
Heft / Ausgabe: | 21 |
Seitenangabe: | 12284-12305 |
Originalveröffentlichung / Quelle: | Nucleic Acids Research (2021) 49:21, 12284-12305.https://doi.org/10.1093/nar/gkab1120 |
DOI: | https://doi.org/10.1093/nar/gkab1120 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit | |
Freie Schlagwort(e): | SMN; YB-1; actin messenger RNA; comet assay; determining gene-product; enrichment; genome wide; interacts; nuclear ribonucleoprotein-R; spinal cord |
Datum der Freischaltung: | 02.05.2022 |
EU-Projektnummer / Contract (GA) number: | 312325 |
OpenAIRE: | OpenAIRE |
Sammlungen: | Open-Access-Publikationsfonds / Förderzeitraum 2021 |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |