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 stresses. 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 to produce transcripts encoding two isoforms: a full-length protein and a shorter form lacking the N-terminal acidic domain. While the neuronal defects produced by total hnRNP R depletion have been investigated before, the individual functions of each hnRNP R isoforms are unknown. We generated a Hnrnpr knockout mouse (Hnrnprtm1a/tm1a) showing selective loss of the full-length hnRNP R isoform. Motoneurons cultured from Hnrnprtm1a/tm1a mice did not show any axonal growth defects. However, they show an accumulation of double-strand breaks and an impaired DNA damage response. Proteomic analysis of the hnRNP R interactome revealed the multifunctional protein Yb1 as a top interactor. Yb1 depleted motoneurons also exhibit defects in DNA damage repair. We show that Yb1 is recruited to chromatin upon DNA damage, 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 Nterminal acidic domain in this context.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Mario Oroshi  

LAB HEAD: Matthias Mann

PROVIDER: PXD026407 | Pride | 2021-11-01

REPOSITORIES: Pride