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RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels.
Müller, Juliane S; Burns, David T; Griffin, Helen; Wells, Graeme R; Zendah, Romance A; Munro, Benjamin; Schneider, Claudia; Horvath, Rita.
Affiliation
  • Müller JS; Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
  • Burns DT; Department of Clinical Neurosciences, University of Cambridge School of Clinical Medicine, Cambridge, UK.
  • Griffin H; Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
  • Wells GR; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • Zendah RA; Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
  • Munro B; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • Schneider C; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • Horvath R; Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
Life Sci Alliance ; 3(8)2020 08.
Article in En | MEDLINE | ID: mdl-32527837
ABSTRACT
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ribosomes / Cerebellar Diseases / Exosome Multienzyme Ribonuclease Complex Type of study: Prognostic_studies Limits: Adult / Animals / Female / Humans / Male Language: En Journal: Life Sci Alliance Year: 2020 Document type: Article Affiliation country: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ribosomes / Cerebellar Diseases / Exosome Multienzyme Ribonuclease Complex Type of study: Prognostic_studies Limits: Adult / Animals / Female / Humans / Male Language: En Journal: Life Sci Alliance Year: 2020 Document type: Article Affiliation country: United kingdom