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Specificity for adenine is established during the hydrolytic cycle of poly(A)-specific ribonuclease (PARN): Mechanism for poly(A) selectivity by PARN
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. (Anders Virtanen)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
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(English)In: Article in journal, Editorial material (Refereed) Submitted
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-392781OAI: oai:DiVA.org:uu-392781DiVA, id: diva2:1349729
Available from: 2019-09-09 Created: 2019-09-09 Last updated: 2019-09-12
In thesis
1. PARN – The Tail End: Function and mechanisms of specificity and processivity
Open this publication in new window or tab >>PARN – The Tail End: Function and mechanisms of specificity and processivity
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Poly(A)-specific ribonuclease (PARN) is an exoribonuclease that is processive, poly(A) specific and cap-binding. PARN deadenylates the poly(A) tails present on a subset of mRNAs and non-coding RNAs, including among others certain snoRNAs, miRNAs and precursor rRNAs. 

Here, we have investigated molecular mechanisms behind PARN’s specificity for adenine and ribose, essential properties for PARN’s ability to degrade poly(A) on RNAs. We have applied enzyme kinetics and used divalent metal ions as mechanistic probes to show that PARN’s poly(A) specificity is tightly linked to a translocation event during the hydrolytic cycle of PARN action. 

To further understand the mechanism of PARN’s processive mode of action we are developing a kinetic model that allow us to measure the probability of processive action for each round of the hydrolytic cycle. Our kinetic model will be general and applicable to the processive action of any processive enzymatic activity. In conclusion, our study has so far established a mechanistic link between PARN’s processive mode of action, hydrolytic activity and preference for degrading poly(A). 

Human patients with genetic lesions in PARN suffer from a spectrum of syndromes called telomere biology disorders (TBD), which are associated with short telomeres. PARN is involved in the maturation of the snoRNA telomerase RNA component (TERC) that is used as template during the elongation of the telomer by the telomerase. Point mutations in the gene for PARN have been identified in patients. We show that point mutations in PARN that perturb its deadenylation activity correlated with TBDs and developmental disorders.

Our mechanistic studies of PARN action will provide a framework for our understanding of PARN’s physiological role and in extension the molecular basis for human diseases caused by perturbed PARN action. Our studies will also be of general interest for our detailed and mechanistic understanding of basic and essential mechanisms of gene expression and RNA biology.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 46
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1854
Keywords
Poly(A) specific ribonuclease, Adenosine, Specificity, Processivty, Telomere biology disorders
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Cellbiology
Identifiers
urn:nbn:se:uu:diva-392998 (URN)978-91-513-0752-7 (ISBN)
Public defence
2019-10-31, B:21, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2019-10-08 Created: 2019-09-12 Last updated: 2019-10-15

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CiteExportLink to record
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