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

ABSTRACT: The eukaryotic RNA exosome is a ubiquitously expressed complex of nine core proteins (EXOSC1-9) and associated nucleases responsible for RNA processing and degradation. Autosomal recessive mutations in EXOSC3, EXOSC8, EXOSC9 and the exosome cofactor RBM7 cause pontocerebellar hypoplasia and motor neuronopathy. To understand the importance of the exosome in neurodegeneration, 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 upregulated in zebrafish lines with homozygous mutations of exosc8 or exosc9, respectively. In addition, exosome deficiency leads to increased levels of multiple non-coding RNAs (e.g. tRNAs, snoRNAs, scaRNAs). 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. Downregulation of EXOSC9 in human cells leads to p53 protein stabilisation and G2/M cell cycle arrest. The work provides explanation for the pathogenesis of exosome-related disorders and highlights the link between exosome function, ribosome biogenesis and p53-dependent signalling.

ORGANISM(S): Danio rerio Homo sapiens

PROVIDER: GSE151452 | GEO | 2020/05/30

REPOSITORIES: GEO

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Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia

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

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

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The RNA helicase DDX1 associates with the nuclear RNA exosome and modulates R-loops [DRIP-seq]

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