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Unique catalytic properties of native human poly(A) polymerase isoforms
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-89789OAI: oai:DiVA.org:uu-89789DiVA: diva2:161539
Available from: 2002-04-05 Created: 2002-04-05 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Functional Significance of Multiple Poly(A) Polymerases (PAPs)
Open this publication in new window or tab >>Functional Significance of Multiple Poly(A) Polymerases (PAPs)
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

3’ end cleavage and polyadenylation are important steps in the maturation of eukaryotic mRNAs. Poly(A) polymerase (PAP), the enzyme catalysing the addition of adenosine residues, exists in multiple isoforms. In this study the functional significance of multiple poly(A) polymerases have been investigated. It is concluded (i) that at least three mechanisms generate the multiple isoforms i.e. gene duplication, post-translational modification and alternative mRNA processing and (ii) that the different isoforms of poly(A) polymerases have different catalytic properties. The study highlights regulation of poly(A) polymerase activity through modulation of its affinity for the substrate as visualised by the KM parameter. We suggest that trans-acting factors modulating the KM of poly(A) polymerase will play important roles in regulating its activity.

A new human poly(A) polymerase (PAPγ) encoded by the PAPOLG gene was identified. PAPγ is 65% homologous to the previously identified PAP. In human cells three isoforms of poly(A) polymerases being 90, 100 and 106 kDa in sizes are present. These native isoforms were purified. The PAPOLA gene encoded the 100 and 106 kDa isoforms while the 90 kDa isoform was encoded by the PAPOLG gene. Native PAPγ was found to be more active than 100 kDa PAP while the hyperphosphorylated 106 kDa PAP isoform was comparably inactive due to a 500-fold decrease in affinity for the RNA substrate.

The PAPOLG gene was shown to encode one unique mRNA while the PAPOLA gene generated five different PAP mRNAs by alternative splicing of the last three exons. The PAPOLA encoded mRNAs were divided into two classes based on the composition of the last three exons. Poly(A) polymerases from the two classes were shown to differ in polyadenylation activities. These differences revealed two novel regulatory motifs in the extreme C-terminal end of PAP, one being inactivating and the other activating for polyadenylation activity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2002. 53 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1140
Genetics, poly(A) polymerase, PAP, phosphorylation, isoforms, alternative splicing, kinetic parameters, hyperphosphorylation, regulation, Genetik, Poly(A) polymeras, PAP, fosforylering, isoformer, alternativ splitsning, kinetiska parametrar, reglering
National Category
Medical Genetics
Research subject
Molecular Cellbiology
urn:nbn:se:uu:diva-1952 (URN)91-554-5285-X (ISBN)
Public defence
2002-04-29, C10:305, Uppsala, 09:15
Available from: 2002-04-05 Created: 2002-04-05Bibliographically approved

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