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Loss of full-length hnRNP R isoform impairs DNA damage response in motoneurons by inhibiting Yb1 recruitment to chromatin

MPS-Authors
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Bader,  Jakob
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Hornburg,  Daniel
Meissner, Felix / Experimental Systems Immunology, Max Planck Institute of Biochemistry, Max Planck Society;

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Meissner,  Felix
Meissner, Felix / Experimental Systems Immunology, Max Planck Institute of Biochemistry, Max Planck Society;

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Mann,  Matthias
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Fulltext (public)

gkab1120.pdf
(Publisher version), 5MB

Supplementary Material (public)

gkab1120_supplemental_files.zip
(Supplementary material), 5MB

Citation

Ghanawi, H., Hennlein, L., Zare, A., Bader, J., Salehi, S., Hornburg, D., et al. (2021). Loss of full-length hnRNP R isoform impairs DNA damage response in motoneurons by inhibiting Yb1 recruitment to chromatin. Nucleic Acids Research, 49(21), 12284-12305. doi:10.1093/nar/gkab1120.


Cite as: http://hdl.handle.net/21.11116/0000-000A-0FDA-1
Abstract
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 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.