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The cytoplasmic mRNA degradation factor Pat1 is required for rRNA processing
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).ORCID iD: 0000-0003-0482-0543
2016 (English)In: RNA Biology, ISSN 1547-6286, Vol. 13, no 4, 455-465 p.Article in journal (Refereed) Published
Abstract [en]

Pat1 is a key cytoplasmic mRNA degradation factor, the loss of which severely increases mRNA half-lives. Several recent studies have shown that Pat1 can enter the nucleus and can shuttle between the nucleus and the cytoplasm. As a result, many nuclear roles have been proposed for Pat1. In this study, we analyzed four previously suggested nuclear roles of Pat1 and show that Pat1 is not required for efficient pre-mRNA splicing or pre-mRNA decay in yeast. However, lack of Pat1 results in accumulation of pre-rRNA processing intermediates. Intriguingly, we identified a novel genetic relationship between Pat1 and the rRNA decay machinery, specifically the exosome and the TRAMP complex. While the pre-rRNA processing intermediates that accumulate in the pat1 deletion mutant are, at least to some extent, recognized as aberrant by the rRNA degradation machinery, it is unlikely that these accumulations are the cause of their synthetic sick relationship. Here, we show that the dysregulation of the levels of mRNAs related to ribosome biogenesis could be the cause of the accumulation of the pre-rRNA processing intermediates.Although our results support a role for Pat1 in transcription, they nevertheless suggest that the primary cause of the dysregulated mRNA levels is most likely due to Pat1’s role in mRNA decapping and mRNA degradation.

Place, publisher, year, edition, pages
Taylor & Francis, 2016. Vol. 13, no 4, 455-465 p.
Keyword [en]
Lsm1-7, mRNA decapping, Pat1, ribosome biogenesis, rRNA, Rrp6, transcription, Trf4
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-118072DOI: 10.1080/15476286.2016.1154253ISI: 000373943500008PubMedID: 26918764OAI: oai:DiVA.org:umu-118072DiVA: diva2:911357
Funder
Swedish Research Council, 621-2010-4602Carl Tryggers foundation , 11:330
Available from: 2016-03-11 Created: 2016-03-11 Last updated: 2016-11-09Bibliographically approved
In thesis
1. mRNA degradation factors as regulators of the gene expression in Saccharomyces cerevisiae
Open this publication in new window or tab >>mRNA degradation factors as regulators of the gene expression in Saccharomyces cerevisiae
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
mRNA nedbrytningsfaktorer som regulatorer av genexpression i Saccharomyces cerevisiae.
Abstract [en]

Messenger RNA degradation is crucial for the regulation of eukaryotic gene expression. It not only modulates the basal mRNA levels but also functions as a quality control system, thereby controlling the availability of mRNA for protein synthesis. In Saccharomyces cerevisiae, the first and the rate-limiting step in the process of mRNA degradation is the shortening of the poly(A) tail by deadenylation complex. After the poly(A) tail shortens, mRNA can be degraded either through the major 5' to 3' decapping dependent or the 3' to 5' exosome-mediated degradation pathway. In this thesis, we show some of the means by which mRNA decay factors can modulate gene expression.

First, Pat1 is a major cytoplasmic mRNA decay factor that can enter the nucleus and nucleo-cytoplasmically shuttle.  Recent evidence suggested several possible nuclear roles for Pat1. We analyzed them and showed that Pat1 might not function in pre-mRNA decay or pre-mRNA splicing, but it is required for normal rRNA processing and transcriptional elongation. We show that the mRNA levels of the genes related to ribosome biogenesis are dysregulated in the strain lacking Pat1, a possible cause of the defective pre-rRNA processing. In conclusion, we theorize that Pat1 might regulate gene expression both at the level of transcription and mRNA decay.

Second, Edc3 and Lsm4 are mRNA decapping activators and mRNA decay factors that function in the assembly of RNA granules termed P bodies. Mutations in mRNA degradation factors stabilize mRNA genome-wide or stabilize individual mRNAs. We demonstrated that paradoxically, deletion of Edc3 together with the glutamine/asparagine-rich domain of Lsm4 led to a decrease in mRNA stability. We believe that the decapping activator Edc3 and the glutamine/asparagine-rich domain of Lsm4 functions together, to modify mRNA decay pathway by altering cellular mRNA decay protein abundance or changing the mRNP composition or by regulating P bodies, to enhance mRNA stability.

Finally, mRNA decay was recently suggested to occur on translating ribosomes or within P bodies. We showed that mRNA degradation factors associate with large structures in sucrose density gradients and this association is resistant to salt and sensitive to detergent. In flotation assay, mRNA decay factors had buoyancy consistent with membrane association, and this association is independent of stress, translation, P body formation or RNA. We believe that such localization of mRNA degradation to membranes may have important implications in gene expression.

In conclusion, this thesis adds to the increasing evidence of the importance of the mRNA degradation factors in the gene expression.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2016. 66 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1844
Keyword
mRNA decapping, mRNA degradation, Pat1, Edc3, Lsm4, Lsm1-7, P bodies, Dcp2, Transcription, Ribosome biogenesis, Exosome.
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-127358 (URN)978-91-7601-560-5 (ISBN)
Public defence
2016-11-02, Hörsal E04, Unod R01, Umeå University, Umeå, 13:00 (English)
Opponent
Supervisors
Funder
Swedish Research CouncilCarl Tryggers foundation
Available from: 2016-11-11 Created: 2016-11-09 Last updated: 2016-11-24Bibliographically approved

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