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Characterization of a non-canonical 5’ capped adenoviral small RNA that is functionally active
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Göran Akusärvi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-282954OAI: oai:DiVA.org:uu-282954DiVA: diva2:918161
Available from: 2016-04-11 Created: 2016-04-08 Last updated: 2016-06-01
In thesis
1. Adenoviral small non-coding RNAs: A Structural and Functional Charaterization
Open this publication in new window or tab >>Adenoviral small non-coding RNAs: A Structural and Functional Charaterization
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Since their discovery in 1953, adenoviruses have significantly contributed to the understanding of virus-host cell interactions, including mechanistic details of cellular processes such as cell cycle control and alternative RNA splicing. Among the first characterized adenoviral genes were the virus-associated RNAs (VA RNAI/II), which are produced in massive amount during a lytic infection. The VA RNAs perform multiple functions and are required for a successful adenovirus life cycle. More recently, it was shown that the VA RNAs are processed into small viral miRNAs, so-called mivaRNAs, which interfere with the function of the cellular RNAi/miRNA machinery.

In papers I and II, we focused on a structural and functional characterization of the mivaRNAs using two approaches. Firstly, we created a model system where the predicted miRNA-like function of mivaRNAI could be investigated, without interfering with other VA RNA functions. This was accomplished by construction of recombinant adenoviruses, in which the seed sequence of mivaRNAI was altered. The results showed that in cell culture experiments the mivaRNAI seed sequence mutants grew as the wild type virus, suggesting that the mivaRNAs are not required during the lytic phase of an adenovirus infection. Secondly, we showed that the VA RNAs from different human adenoviruses (Ad4, Ad5, Ad11 and Ad37) undergo the same type of Dicer-dependent processing into mivaRNAs, which subsequently are loaded onto the RNA induced silencing complex (RISC), albeit with different efficiencies.

In paper III, we demonstrated that the promoter proximal region of the adenovirus major late promoter (MLP) produces a novel non-canonical class of small RNAs, which we termed the MLP-TSS-sRNAs. Surprisingly the MLP-TSS-sRNA maintains the m7G-cap structure while bound to Ago2 containing RISC. These complexes are functional suppressing expression of target mRNAs with complementary binding site. Most importantly, the MLP-TSS-sRNA limits the efficiency of viral DNA replication probably through a targeting of the E2B mRNAs, which are transcribed in the antisense orientation. In conclusion, the MLP-TSS-sRNA represents the first viral small RNA, which has been shown to have a function as a regulator of an adenovirus infection.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 49 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1216
Keyword
non-coding RNA miRNA mivaRNA canonical Dicer Ago2 TSS m7G Cap Adenovirus replication E2B
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-283080 (URN)978-91-554-9556-5 (ISBN)
Public defence
2016-06-02, B/A1:111a, BMC, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2016-05-11 Created: 2016-04-11 Last updated: 2016-06-01

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