Loss of full-length hnRNP R isoform impairs DNA damage response in motoneurons by inhibiting Yb1 recruitment to chromatin
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Loss of full-length hnRNP R isoform impairs DNA damage response in motoneurons by inhibiting Yb1 recruitment to chromatin. / Ghanawi, Hanaa; Hennlein, Luisa; Zare, Abdolhossein; Bader, Jakob; Salehi, Saeede; Hornburg, Daniel; Ji, Changhe; Sivadasan, Rajeeve; Drepper, Carsten; Meissner, Felix; Mann, Matthias; Jablonka, Sibylle; Briese, Michael; Sendtner, Michael.
I: Nucleic Acids Symposium Series, Bind 49, Nr. 21, 2021, s. 12284-12305.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Loss of full-length hnRNP R isoform impairs DNA damage response in motoneurons by inhibiting Yb1 recruitment to chromatin
AU - Ghanawi, Hanaa
AU - Hennlein, Luisa
AU - Zare, Abdolhossein
AU - Bader, Jakob
AU - Salehi, Saeede
AU - Hornburg, Daniel
AU - Ji, Changhe
AU - Sivadasan, Rajeeve
AU - Drepper, Carsten
AU - Meissner, Felix
AU - Mann, Matthias
AU - Jablonka, Sibylle
AU - Briese, Michael
AU - Sendtner, Michael
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - NUCLEAR RIBONUCLEOPROTEIN-R
KW - DETERMINING GENE-PRODUCT
KW - ACTIN MESSENGER-RNA
KW - COMET ASSAY
KW - GENOME-WIDE
KW - SPINAL-CORD
KW - YB-1
KW - SMN
KW - INTERACTS
KW - ENRICHMENT
U2 - 10.1093/nar/gkab1120
DO - 10.1093/nar/gkab1120
M3 - Journal article
C2 - 34850154
VL - 49
SP - 12284
EP - 12305
JO - Nucleic acids symposium series
JF - Nucleic acids symposium series
SN - 0261-3166
IS - 21
ER -
ID: 288925690