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Specific inactivation of inhibitory sequences in the 5' end of the human papillomavirus type 16 L1 open reading frame results in production of high levels of L1 protein in human epithelial cells
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2002 In: Journal of Virology, ISSN 11861841, Vol. Mars, no 76, 2739-52 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2002. Vol. Mars, no 76, 2739-52 p.
Identifiers
URN: urn:nbn:se:uu:diva-92572OAI: oai:DiVA.org:uu-92572DiVA: diva2:165706
Available from: 2005-02-04 Created: 2005-02-04Bibliographically approved
In thesis
1. The Role of Polyadenylation in Human Papillomavirus Type 16 Late Gene Expression
Open this publication in new window or tab >>The Role of Polyadenylation in Human Papillomavirus Type 16 Late Gene Expression
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

High-risk type human papillomaviruses (HPVs) are associated with cancer. HPVs are strictly epitheliotropic and infect basal cell layers, establishing a life cycle strongly linked to the differentiation stage of the infected cells. The viral capsid late genes, L2 and L1, are only expressed in terminally differentiated epithelium. Late gene expression involves regulation of most gene processing events including transcription, splicing, polyadenylation, mRNA stability and translation.

Both L2 and L1 have elements present in the open reading frames (ORFs) negatively affecting mRNA levels and translation. The negative elements in L1 were mapped to the first 514 nucleotides, with the strongest inhibitory effect located in the first 129 nucleotides. The negative elements in the L2 sequence were concentrated in two locations on the gene. Both genes were mutated by changing the nucleotide sequence while retaining the amino acid sequence. Mutating the first 514 nucleotides in L1 deactivated the negative elements while the entire L2 gene had to be mutated to achieve the same result. The L2 protein was found to localise the L1 protein into a punctuated pattern in the nucleus.

In the HPV-16 genome the negative elements reside in regions important for regulation of polyadenylation and splicing, critical for late gene expression. By exchanging parts of the L2 gene in subgenomic constructs with the corresponding mutant sequence we show that certain features of the L2 elements direct splicing to the L1 splice acceptor, and also regulate the efficiency of the early polyadenylation site. Cumulative binding of hnRNP H to the L2 mRNA gradually increased polyadenylation efficiency. Most interestingly, hnRNP H levels were downregulated in more differentiated epithelial cells.

Elucidation of how expression of the immunogenic late proteins is regulated would be greatly beneficial in prevention and treatment of HPV infection and thereby cancer.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 82 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 4
Keyword
Molecular biology, HPV-16, polyadenylation, mRNA stability, codon usage, hnRNP H, DSE, splicing, negative element, RNA processing, Molekylärbiologi
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-4774 (URN)91-554-6141-7 (ISBN)
Public defence
2005-02-25, B42, Biomedicinska centret, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2005-02-04 Created: 2005-02-04Bibliographically approved

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