Nuclear Export and Translation of Circular Repeat-containing Intronic RNA in C9ORF72-ALS/FTD

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Aug 14

PMID 34389711

Citations 34

Authors

Shaopeng Wang

Malgorzata J Latallo

Zhe Zhang

Bo Huang

Dmitriy G Bobrovnikov

Daoyuan Dong

Nathan M Livingston

Wilson Tjoeng

Lindsey R Hayes

Jeffrey D Rothstein

Lyle W Ostrow

Bin Wu

Shuying Sun

Affiliations

Soon will be listed here.

Abstract

C9ORF72 hexanucleotide GGGGCC repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat-containing RNA mediates toxicity through nuclear granules and dipeptide repeat (DPR) proteins produced by repeat-associated non-AUG translation. However, it remains unclear how the intron-localized repeats are exported and translated in the cytoplasm. We use single molecule imaging approach to examine the molecular identity and spatiotemporal dynamics of the repeat RNA. We demonstrate that the spliced intron with G-rich repeats is stabilized in a circular form due to defective lariat debranching. The spliced circular intron, instead of pre-mRNA, serves as the translation template. The NXF1-NXT1 pathway plays an important role in the nuclear export of the circular intron and modulates toxic DPR production. This study reveals an uncharacterized disease-causing RNA species mediated by repeat expansion and demonstrates the importance of RNA spatial localization to understand disease etiology.

Citing Articles

Circular RNAs in neurological conditions - computational identification, functional validation, and potential clinical applications.

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Nuclear mRNA export.

Chen S, Jiang Q, Fan J, Cheng H Acta Biochim Biophys Sin (Shanghai). 2024; 57(1):84-100.

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