Transcriptome-wide RNA binding analysis of C9orf72 poly(PR) dipeptidesMore about Open Access at the Crick
Authors listRubika Balendra Igor Ruiz De Los Mozos Hana M Odeh Idoia Glaria Carmelo Milioto Katherine M Wilson Agnieszka M Ule Martina Hallegger Laura Masino Stephen Martin Rickie Patani James Shorter Jernej Ule Adrian M Isaacs
An intronic GGGGCC repeat expansion in C9orf72 is a common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeats are transcribed in both sense and antisense directions to generate distinct dipeptide repeat proteins, of which poly(GA), poly(GR), and poly(PR) have been implicated in contributing to neurodegeneration. Poly(PR) binding to RNA may contribute to toxicity, but analysis of poly(PR)-RNA binding on a transcriptome-wide scale has not yet been carried out. We therefore performed crosslinking and immunoprecipitation (CLIP) analysis in human cells to identify the RNA binding sites of poly(PR). We found that poly(PR) binds to nearly 600 RNAs, with the sequence GAAGA enriched at the binding sites. In vitro experiments showed that poly(GAAGA) RNA binds poly(PR) with higher affinity than control RNA and induces the phase separation of poly(PR) into condensates. These data indicate that poly(PR) preferentially binds to poly(GAAGA)-containing RNAs, which may have physiological consequences.
Journal Life Science Alliance
Issue number 9