PT  - JOURNAL ARTICLE
AU  - Juliane S Müller
AU  - David T Burns
AU  - Helen Griffin
AU  - Graeme R Wells
AU  - Romance A Zendah
AU  - Benjamin Munro
AU  - Claudia Schneider
AU  - Rita Horvath
TI  - RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels
AID  - 10.26508/lsa.202000678
DP  - 2020 Aug 01
TA  - Life Science Alliance
PG  - e202000678
VI  - 3
IP  - 8
4099  - https://www.life-science-alliance.org/content/3/8/e202000678.short
4100  - https://www.life-science-alliance.org/content/3/8/e202000678.full
SO  - Life Sci. Alliance2020 Aug 01; 3
AB  - 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.