RT Journal Article SR Electronic T1 RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202000678 DO 10.26508/lsa.202000678 VO 3 IS 8 A1 Juliane S Müller A1 David T Burns A1 Helen Griffin A1 Graeme R Wells A1 Romance A Zendah A1 Benjamin Munro A1 Claudia Schneider A1 Rita Horvath YR 2020 UL https://www.life-science-alliance.org/content/3/8/e202000678.abstract 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.