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

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 (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.

hnRNP R negatively regulates transcription by modulating the association of P‐TEFb with 7SK and BRD4

“…Heterogeneous nuclear ribonucleoproteins are often differentially expressed between tissues. For example, hnRNP R is enriched in the nervous system (Ghanawi et al , 2021). It is therefore possible that the relative amounts of individual 7SK/hnRNP complexes differ between distinct organs, contributing to cell‐type‐specific expression profiles.…”

Autophagy activity is inhibited by hnRNP R

“…hnRNP R is a heterogeneous nuclear ribonucleoprotein, which was found mostly in the nuclear and has important functions on transcription, splicing and mRNA transportation [46][47][48][49].…”

“…hnRNP R is a heterogeneous nuclear ribonucleoprotein, which was found mostly in the nuclear and has important functions on transcription, splicing and mRNA transportation[46-49]. Besides that, hnRNP R can also be found in the cytosol and motoneuron axons[47, 48, 50], which plays important role in mRNA translation, mRNP transport and stress granule formation[51].…”

High expression of HNRNPR in ESCA combined with 18F-FDG PET/CT metabolic parameters are novel biomarkers for preoperative diagnosis of ESCA

“…Previous studies have demonstrated that the level of expression of this family varies across cancers, implying that they play an important role in tumorigenesis. HNRNPR has recently shifted its focus to the mechanism of action in the nervous system [ 18 , 19 ]. Although it has been established as a proto-oncogene associated with gastric cancer (GC) [ 20 ], few studies have examined its role in other cancers.…”