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Serine/arginine-rich protein 30c activates human papillomavirus type 16 L1 mRNA expression via a bimodal mechanism
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Stefan Schwartz)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Stefan Schwartz)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Stefan Schwartz)
Dublin Institute of Technology, Kevin Street, Dublin 8, Ireland..
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2011 (English)In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 92, no 10, 2411-2421 p.Article in journal (Refereed) Published
Abstract [en]

Two splice sites on the human papillomavirus type 16 (HPV-16) genome are used exclusively by the late capsid protein L1 mRNAs: SD3632 and SA5639. These splice sites are suppressed in mitotic cells. This study showed that serine/arginine-rich protein 30c (SRp30c), also named SFRS9, activated both SD3632 and SA5639 and induced production of L1 mRNA. Activation of HPV-16 L1 mRNA splicing by SRp30c required an intact arginine/serine-repeat (RS) domain of SRp30c. In addition to this effect, SRp30c could enhance L1 mRNA production indirectly by inhibiting the early 3′-splice site SA3358, which competed with the late 3′-splice site SA5639. SRp30c bound directly to sequences downstream of SA3358, suggesting that SRp30c inhibited the enhancer at SA3358 and caused a redirection of splicing to the late 3′-splice site SA5639. This inhibitory effect of SRp30c was independent of its RS domain. These results suggest that SRp30c can activate HPV-16 L1 mRNA expression via a bimodal mechanism: directly by stimulating splicing to late splice sites and indirectly by inhibiting competing early splice sites.

Place, publisher, year, edition, pages
2011. Vol. 92, no 10, 2411-2421 p.
Keyword [en]
HPV-16, splicing, SR-proteins, SRp30c, polyadenylation
National Category
Microbiology in the medical area
Research subject
Medical Virology
Identifiers
URN: urn:nbn:se:uu:diva-150707DOI: 10.1099/vir.0.033183-0ISI: 000295856000022OAI: oai:DiVA.org:uu-150707DiVA: diva2:408525
Available from: 2011-04-05 Created: 2011-04-04 Last updated: 2017-12-11
In thesis
1. Cellular and Viral Factors that Control Human Papillomavirus Type 16 Late Gene Expression
Open this publication in new window or tab >>Cellular and Viral Factors that Control Human Papillomavirus Type 16 Late Gene Expression
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human papillomavirus type 16 (HPV-16) is the major cause of cervical cancer. We speculate that inhibition of HPV-16 late gene expression is a prerequisite for establishment of persistence and progression to cervical cancer. This is based on the findings that the late proteins are found only in the nuclei of terminally differentiated epithelium, and are never detected in human papillomavirus infected cervical cancer cells. It is therefore of great importance to understand how HPV-16 controls the onset of the immunogenic proteins L1 and L2 in an infected cancer cell. HPV-16 late gene expression is tightly regulated by differentiation-dependent transcription as well as by post-transcriptional mechanisms.

The long-term goal of these studies was to understand how HPV late gene expression is regulated. The specific aim of this thesis was to identify cellular and viral factors that force the virus to switch on the late genes, and to determine the mechanism of action of these factors. This will help us to understand under which circumstances HPV establish persistent infections that could progress to cancer.

We found three cellular factors; PTB, ASF/SF2 and SRp30c, and one viral factor; AdE4orf4, that in four distinctive ways were involved in the regulation of HPV-16 late gene expression. Interestingly, over-expression of PTB, AdE4orf4 or SRp30c produced different types of spliced late mRNAs. PTB induced the unspliced L2/L1 mRNA, while AdE4orf4 and SRp30c induced the spliced L1 and L1i mRNA, respectively. The three proteins had different mechanisms of action and different target sites within the HPV-16 genome, which revealed the many and complex pathways in HPV-16 gene regulation. These findings have contributed to a broader understanding of how the expression of HPV-16 late genes is controlled.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 670
National Category
Microbiology in the medical area
Research subject
Medical Virology
Identifiers
urn:nbn:se:uu:diva-150706 (URN)978-91-554-8069-1 (ISBN)
Public defence
2011-05-31, BMC, C10:305, Husargatan 3, Uppsala, 13:15 (English)
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Available from: 2011-05-10 Created: 2011-04-04 Last updated: 2011-07-01Bibliographically approved

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Somberg, MonikaJohansson, CeciliaSchwartz, Stefan

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