Loss of full-length hnRNP R isoform impairs DNA damage response in motoneurons by inhibiting Yb1 recruitment to chromatin.
Animals
Axons
/ metabolism
Cell Line
Cells, Cultured
Chromatin
/ genetics
DNA Damage
DNA Repair
/ genetics
HEK293 Cells
Heterogeneous-Nuclear Ribonucleoproteins
/ genetics
Humans
Immunoblotting
Mice, Inbred C57BL
Mice, Knockout
Motor Neurons
/ cytology
Protein Binding
Protein Isoforms
/ genetics
Y-Box-Binding Protein 1
/ genetics
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
02 12 2021
02 12 2021
Historique:
accepted:
28
10
2021
revised:
20
10
2021
received:
13
11
2020
pubmed:
2
12
2021
medline:
11
1
2022
entrez:
1
12
2021
Statut:
ppublish
Résumé
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 (Hnrnprtm1a/tm1a) in which expression of full-length hnRNP R was abolished while production of the truncated hnRNP R isoform was retained. Motoneurons cultured from Hnrnprtm1a/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 γ-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.
Identifiants
pubmed: 34850154
pii: 6439689
doi: 10.1093/nar/gkab1120
pmc: PMC8643683
doi:
Substances chimiques
Chromatin
0
Heterogeneous-Nuclear Ribonucleoproteins
0
Hnrpr protein, mouse
0
Protein Isoforms
0
Y-Box-Binding Protein 1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12284-12305Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
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