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A splicing enhancer in the E4 coding region of HPV-16 is required for early mRNA splicing and polyadenylation, as well as inhibition of premature late gene expression
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2005 In: Journal of Virology, ISSN 0022-538X, Vol. 79, no 18, 12002-12015 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2005. Vol. 79, no 18, 12002-12015 p.
Identifiers
URN: urn:nbn:se:uu:diva-93536OAI: oai:DiVA.org:uu-93536DiVA: diva2:167043
Available from: 2005-10-06 Created: 2005-10-06Bibliographically approved
In thesis
1. Regulation of RNA Processing in Human Papillomavirus Type 16
Open this publication in new window or tab >>Regulation of RNA Processing in Human Papillomavirus Type 16
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human papillomavirus type 16 (HPV-16) is the major cause of cervical cancer. HPV-16 gene expression is tightly linked to the differentiation programme of the infected epithelium. Expression of the late genes, L1 and L2, encoding the capsid proteins, is delayed until the more terminally differentiated cells. Successful inhibition of HPV-16 late gene expression early in the viral life cycle is essential for persistence of infection, the highest risk factor for cervical cancer.

The goal of this thesis was to identify regulatory RNA elements and cellular factors that influence RNA processing events, such as alternative splicing and polyadenylation, during late gene expression. For this purpose, transfection of plasmids containing almost the full-length HPV-16 genome into HeLa cells, followed by RNA analysis, was employed. An exonic splicing enhancer (ESE) was identified that firmly supported the use of the E4 3’ splice site. A key regulator of HPV-16 gene expression, the E4 ESE was required for early mRNA splicing and polyadenylation, as well as for inhibition of premature late gene expression. The early polyadenylation signal (pAE) is also an important block of premature late gene expression. An upstream polyadenylation element (USE) was identified in the early 3’ untranslated region that enhanced polyadenylation at pAE, and interacted specifically with the cellular factors CstF-64, hnRNP C1/C2, PTB and hFip1. With the help of adenoviral E4orf4, a protein which causes dephosphorylation of SR proteins, we found that overexpression of SRp30c activated HPV-16 late gene expression by an exon skipping mechanism, and that SRp30c may interfere with early mRNA terminal exon definition.

This work identified a crucial splicing enhancer, as well as a number of cellular proteins binding to an USE in the early region of HPV-16. Furthermore, the cellular splicing factor SRp30c was shown to play a role in the regulation of HPV-16 late gene expression.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 77 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 75
Keyword
Molecular biology, RNA processing, human papillomavirus, HPV-16, alternative splicing, polyadenylation, exonic splicing enhancer, 3'UTR, upstream polyadenylation element, SR proteins, Molekylärbiologi
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-5972 (URN)91-554-6356-8 (ISBN)
Public defence
2005-10-27, Room B42, BMC, Husargatan 3, Uppsala, 10:00
Opponent
Supervisors
Available from: 2005-10-06 Created: 2005-10-06Bibliographically approved

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