The Exosome Component Rrp6 Is Required for RNA Polymerase II Termination at Specific Targets of the Nrd1-Nab3 Pathway
Open accessAbstract
The exosome and its nuclear specific subunit Rrp6 form a 3'-5' exonuclease complex that regulates diverse aspects of RNA biology including 3' end processing and degradation of a variety of noncoding RNAs (ncRNAs) and unstable transcripts. Known targets of the nuclear exosome include short (<1000 bp) RNAPII transcripts such as small noncoding RNAs (snRNAs), cryptic unstable transcripts (CUTs), and some stable unannotated transcripts (SUTs) that are terminated by an Nrd1, Nab3, and Sen1 (NNS) dependent mechanism. NNS-dependent termination is coupled to RNA 3' end processing and/or degradation by the Rrp6/exosome in yeast. Recent work suggests Nrd1 is necessary for transcriptome surveillance, regulating promoter directionality and suppressing antisense transcription independently of, or prior to, Rrp6 activity. It remains unclear whether Rrp6 is directly involved in termination; however, Rrp6 has been implicated in the 3' end processing and degradation of ncRNA transcripts including CUTs. To determine the role of Rrp6 in NNS termination globally, we performed RNA sequencing (RNA-Seq) on total RNA and perform ChIP-exo analysis of RNA Polymerase II (RNAPII) localization. Deletion of RRP6 promotes hyper-elongation of multiple NNS-dependent transcripts resulting from both improperly processed 3' RNA ends and faulty transcript termination at specific target genes. The defects in RNAPII termination cause transcriptome-wide changes in mRNA expression through transcription interference and/or antisense repression, similar to previously reported effects of depleting Nrd1 from the nucleus. Elongated transcripts were identified within all classes of known NNS targets with the largest changes in transcription termination occurring at CUTs. Interestingly, the extended transcripts that we have detected in our studies show remarkable similarity to Nrd1-unterminated transcripts at many locations, suggesting that Rrp6 acts with the NNS complex globally to promote transcription termination in addition to 3' end RNA processing and/or degradation at specific targets.
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Many transcripts differentially expressed in all five datasets were noncoding RNAs, which are well established targets for the RNA exosome and can include PROMPTs, antisense transcripts, and long noncoding RNAs.
“Many of the transcripts that were differentially expressed in all five datasets were noncoding RNAs, which are well established to be targets for the RNA exosome and can include PROMPTs, antisense (AS) transcripts, and long noncoding RNAs (lncRNAs) as shown in Fig. 2B61–67.”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [65]
The Introduction (page unavailable) says the nuclear exosome degrades CUTs, and the Results (page unavailable) report an antisense noncoding transcript upregulated after RRP6 deletion. The Introduction also identifies CUT281 as an antisense long noncoding RNA. Our copy does not identify PROMPTs as exosome targets; the statement about transcripts shared across five datasets belongs to the citing paper's own analysis. (LLM, conf=0.82)
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- Authors
- Fox, M. J., Gao, H., Smith-Kinnaman, W. R., Liu, Y., & Mosley, A. L.
- Affiliations
- Indiana University School of Medicine (US)
- Indiana University Indianapolis (US)
- Corresponding author
- Mosley, Amber L.
- Venue
- PLOS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-02-13
- Volume
- 11
- Issue
- 2
- Pages
- e1004999
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC4378619
- OpenAlex
- W2044762155
- Cited by
- 61
- References
- 93
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 8 · 2019: 7 · 2018: 6 · 2017: 7 · 2016: 7 · 2015: 9 · 2012: 1
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- Purdue University Indianapolis (Indiana University) (submittedVersion, cc-by)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- Eli Lilly and Company
- Emory University
- Lilly Endowment
- School of Medicine, Indiana University
- National Institute of General Medical Sciences (R01GM099714, GM099714)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- Rrp6, exosomes, RNA polymerase II termination, cryptic unstable transcripts, small RNA, RNA 3' end processing, antisense transcription, transcription elongation, Saccharomyces cerevisiae, ChIP-exo, RNA degradation
- MeSH terms
- DNA Helicases, Nuclear Proteins, RNA Polymerase II, Saccharomyces cerevisiae, Transcription, Genetic, Gene Expression Regulation, Fungal, RNA-Binding Proteins, RNA Helicases, RNA, Untranslated, Saccharomyces cerevisiae Proteins, Exosomes, Transcriptome, Exosome Multienzyme Ribonuclease Complex
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