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Rapid Depletion of DIS3, EXOSC10, or XRN2 Reveals the Immediate Impact of Exoribonucleolysis on Nuclear RNA Metabolism and Transcriptional Control.

Authors
  • Davidson, Lee1
  • Francis, Laura1
  • Cordiner, Ross A2
  • Eaton, Joshua D1
  • Estell, Chris1
  • Macias, Sara2
  • Cáceres, Javier F2
  • West, Steven3
  • 1 The Living Systems Institute, University of Exeter, Stocker Rd, Exeter EX4 4QD, UK.
  • 2 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • 3 The Living Systems Institute, University of Exeter, Stocker Rd, Exeter EX4 4QD, UK. Electronic address: [email protected]
Type
Published Article
Journal
Cell Reports
Publisher
Elsevier
Publication Date
Mar 05, 2019
Volume
26
Issue
10
Identifiers
DOI: 10.1016/j.celrep.2019.02.012
PMID: 30840897
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Cell-based studies of human ribonucleases traditionally rely on methods that deplete proteins slowly. We engineered cells in which the 3'→5' exoribonucleases of the exosome complex, DIS3 and EXOSC10, can be rapidly eliminated to assess their immediate roles in nuclear RNA biology. The loss of DIS3 has the greatest impact, causing the substantial accumulation of thousands of transcripts within 60 min. These transcripts include enhancer RNAs, promoter upstream transcripts (PROMPTs), and products of premature cleavage and polyadenylation (PCPA). These transcripts are unaffected by the rapid loss of EXOSC10, suggesting that they are rarely targeted to it. More direct detection of EXOSC10-bound transcripts revealed its substrates to prominently include short 3' extended ribosomal and small nucleolar RNAs. Finally, the 5'→3' exoribonuclease, XRN2, has little activity on exosome substrates, but its elimination uncovers different mechanisms for the early termination of transcription from protein-coding gene promoters. Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

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