RT Journal Article
SR Electronic
T1 Transcriptome-wide RNA binding analysis of C9orf72 poly(PR) dipeptides
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202201824
DO 10.26508/lsa.202201824
VO 6
IS 9
A1 Balendra, Rubika
A1 Ruiz de los Mozos, Igor
A1 Odeh, Hana M
A1 Glaria, Idoia
A1 Milioto, Carmelo
A1 Wilson, Katherine M
A1 Ule, Agnieszka M
A1 Hallegger, Martina
A1 Masino, Laura
A1 Martin, Stephen
A1 Patani, Rickie
A1 Shorter, James
A1 Ule, Jernej
A1 Isaacs, Adrian M
YR 2023
UL http://www.life-science-alliance.org/content/6/9/e202201824.abstract
AB 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.