FUS, RNA and the nucleolus

Moore, Duncan Alan (2016) FUS, RNA and the nucleolus. Doctoral thesis (PhD), University of Sussex.

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Abstract

Fused-in-sarcoma (FUS) is an RNA binding protein, thought to be involved in a wide variety of cellular processes, and mutations in FUS are known to be causative for amyotrophic lateral sclerosis (ALS). The mechanism of pathogenesis for ALS has not been established but it has been proposed that dysfunction in cellular functions involving RNA could be responsible. Investigations into a FUS-ALS patient cell line showed sensitivity to the transcriptional inhibitor camptothecin (CPT) and demonstrated constitutively fragmented nucleoli, a phenotype that has been associated with rRNA dysfunction, as well as a possible defect in ribosomal RNA (rRNA) maturation. In addition a reversible relocalisation of FUS to the nucleolus in response to inhibition of RNA polymerase II was observed in all cell lines examined. This relocalisation appeared to be dependent on the activity of phosphodiesterase 8 (PDE8) and on the presence of rRNA, as pre-inhibition of RNAP I (which produces rRNA) prevented relocalisation of FUS. However treatment of both RNAP I and RNAP II at the same time resulted in FUS relocalisation and the protein remaining in the nucleolus for hours if inhibition was maintained - long after RNA would be depleted at the site were RNAP I inhibited in isolation. These findings suggest that FUS may have a role in protecting pre-rRNA transcripts from degradation during transcriptional stress.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: Library Cataloguing
Date Deposited: 19 Dec 2016 14:27
Last Modified: 21 Jan 2019 10:00
URI: http://sro.sussex.ac.uk/id/eprint/65760

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