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RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels

Lookup NU author(s): Dr David Burns, Dr Helen GriffinORCiD, Dr Graeme WellsORCiD, Romance Zendah, Benjamin Munro, Dr Claudia SchneiderORCiD, Professor Rita HorvathORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2020 Müller et al.The RNA exosome is a ubiquitously expressed complex of nine core proteins (EXOSC1-9) and associated nucleases responsible for RNA processing and degradation. Mutations in EXOSC3, EXOSC8, EXOSC9, and the exosome cofactor RBM7 cause pontocerebellar hypoplasia and motor neuronopathy. We investigated the consequences of exosome mutations on RNA metabolism and cellular survival in zebrafish and human cell models. We observed that levels of mRNAs encoding p53 and ribosome biogenesis factors are increased in zebrafish lines with homozygous mutations of exosc8 or exosc9, respectively. Consistent with higher p53 levels, mutant zebrafish have a reduced head size, smaller brain, and cerebellum caused by an increased number of apoptotic cells during development. Down-regulation of EXOSC8 and EXOSC9 in human cells leads to p53 protein stabilisation and G2/M cell cycle arrest. Increased p53 transcript levels were also observed in muscle samples from patients with EXOSC9 mutations. Our work provides explanation for the pathogenesis of exosome-related disorders and highlights the link between exosome function, ribosome biogenesis, and p53-dependent signalling. We suggest that exosome-related disorders could be classified as ribosomopathies.

Publication metadata

Author(s): Muller JS, Burns DT, Griffin H, Wells GR, Zendah RA, Munro B, Schneider C, Horvath R

Publication type: Article

Publication status: Published

Journal: Life Science Alliance

Year: 2020

Volume: 3

Issue: 8

Online publication date: 11/06/2020

Acceptance date: 03/06/2020

Date deposited: 26/06/2020

ISSN (electronic): 2575-1077

Publisher: Life Science Alliance


DOI: 10.26508/lsa.202000678

PubMed id: 32527837


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Funder referenceFunder name
e Biotechnology and Biological Sciences Research Council
Medical Research Council
Wellcome Investigator Fund