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A suppressive effect of Sp1 recruitment to the first leader 5' splice site region on L4-22K-mediated activation of the adenovirus major late promoter
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2015 (English)In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 210, 133-140 p.Article in journal (Refereed) Published
Abstract [en]

Transcription from the adenovirus major late promoter (MLP) requires binding of late phase-specific factors to the so-called DE element located approximately 100 base pairs downstream of the MLP transcriptional start site. The adenovirus L4-22K protein binds to the DE element and stimulates transcription from the MLP via a DE sequence-dependent mechanism. Here we use a transient expression approach to show that L4-22K binds to an additional site downstream of the MLP start site, the so-called R1 region, which includes the major late first leader 5' splice site. Binding of L4-22K to R1 has a suppressive effect on MLP transcription. L4-22K binds to the distal part of R1 and stimulates the recruitment of Sp1 and other cellular factors to a site overlapping the first leader 5' splice site. Binding of Sp1 to the 5' splice site region had an inhibitory effect on L4-22K-activated MLP transcription.

Place, publisher, year, edition, pages
2015. Vol. 210, 133-140 p.
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-275814DOI: 10.1016/j.virusres.2015.07.026ISI: 000365455500020PubMedID: 26247419OAI: oai:DiVA.org:uu-275814DiVA: diva2:901325
Funder
Swedish Cancer Society, 12 0504Swedish Research Council, K2012-99X-21959-01-3 2006-5038-36531-16
Available from: 2016-02-07 Created: 2016-02-07 Last updated: 2017-11-30Bibliographically approved
In thesis
1. The Multifunctional Nature of the Adenovirus L4-22K Protein
Open this publication in new window or tab >>The Multifunctional Nature of the Adenovirus L4-22K Protein
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The adenovirus major late transcription unit (MLTU) encodes for most of the mRNAs that are translated into the structural proteins of the virus capsid. Transcription from the MLTU is directed by the major late promoter (MLP), which is highly activated during the late phase of infection. This thesis discusses how the adenovirus-encoded L4-22K protein regulates the MLP at both the level of transcription and pre-mRNA splicing. The study shed new light on the complex regulation of the early to late shift of adenoviral gene expression.

Here we show that the L4-22K protein has opposing effects on MLP transcription, functioning both as an activator and a repressor protein. The stimulatory effect mainly depends on the direct interaction of the L4-22K protein with the downstream element (DE element) located approximately 100 nucleotides downstream of the transcription initiation site. In addition to the DE element we also show that the promoter-proximal upstream element (UPE) acts as an L4-22K responsive enhancer element in the MLP. Preliminary data suggests that the activation of MLP transcription via DE and UPE differs mechanistically. The transactivation domain of the L4-22K protein is localized to the conserved carboxy-terminus of the protein.

Our results also defined a novel low affinity L4-22K binding site, the R1 region, which functions as a repressor element in MLP transcription. At high concentrations L4-22K binds to R1 and recruits the cellular transcription factor Sp1 to a DNA segment covering the major late first leader 5´ splice site that is embedded in the R1 region. Sp1 binding to R1 results in a suppression of L4-22K-mediated activation of MLP transcription. This self-limiting effect on MLP transcription might have a function to fine-tune the MLTU gene expression.

Interestingly, the L4-22K protein binds with the same sequence specificity to both the R1 double-stranded DNA and R1 single-stranded RNA (ssRNA). L4-22K binds to the R1 ssRNA with the same polarity as the MLTU nascent RNA. This binding results in the recruitment of U1 snRNA to the major late first leader 5´ splice site. This enhanced U1 snRNA recruitment leads to a suppression of MLP transcription and simultaneously an increase of major late first intron splicing.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1185
Keyword
L4-22K, MLP, RNA, transcription, splicing, adenovirus
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-278135 (URN)978-91-554-9486-5 (ISBN)
Public defence
2016-04-15, A1:111a, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2016-03-22 Created: 2016-02-23 Last updated: 2016-04-04

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Lan, SusanPunga, TanelAkusjärvi, Göran

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