Flavivirus 5' UTR

The Flavivirus positive-oriented, single-stranded RNA genome has a length of 10,000 - 11,000 bases. The genus includes human pathogens like Zika virus, West-Nile virus, Dengue virus, Yellow Fever virus and other.{{Cite web|title=International Committee on Taxonomy of Viruses (ICTV)|url=https://ictv.global/taxonomy|access-date=2020-08-14|website=talk.ictvonline.org|language=en}}

The 5' UTR of flaviviruses are highly structured, has a length of approximately 100 nucleotides and harbors two conserved RNA secondary structures which are vital for the viral life cycle.{{Cite journal|last1=Ng|first1=Wy|last2=Soto-Acosta|first2=Ruben|last3=Bradrick|first3=Shelton|last4=Garcia-Blanco|first4=Mariano|last5=Ooi|first5=Eng|date=2017-06-06|title=The 5′ and 3′ Untranslated Regions of the Flaviviral Genome|journal=Viruses|language=en|volume=9|issue=6|pages=137|doi=10.3390/v9060137|issn=1999-4915|pmc=5490814|pmid=28587300|doi-access=free}}{{Cite journal|last1=Gebhard|first1=Leopoldo G.|last2=Filomatori|first2=Claudia V.|last3=Gamarnik|first3=Andrea V.|date=2011-09-15|title=Functional RNA Elements in the Dengue Virus Genome|journal=Viruses|language=en|volume=3|issue=9|pages=1739–1756|doi=10.3390/v3091739|issn=1999-4915|pmc=3187688|pmid=21994804|doi-access=free}} During replication, the 5' UTR interacts with the 3' UTR of the genome to initiate synthesis of new viral replicates and viral protein translation. In direct adjacency to the 5' UTR lies the cHP structure, which is essential for the viral replication.{{Cite journal|last1=Zeng|first1=Miao|last2=Duan|first2=Yanping|last3=Zhang|first3=Wei|last4=Wang|first4=Mingshu|last5=Jia|first5=Renyong|last6=Zhu|first6=Dekang|last7=Liu|first7=Mafeng|last8=Zhao|first8=Xinxin|last9=Yang|first9=Qiao|last10=Wu|first10=Ying|last11=Zhang|first11=Shaqiu|date=2020-03-27|title=Universal RNA Secondary Structure Insight Into Mosquito-Borne Flavivirus (MBFV) cis-Acting RNA Biology|journal=Frontiers in Microbiology|volume=11|pages=473|doi=10.3389/fmicb.2020.00473|pmid=32292394|pmc=7118588|issn=1664-302X|doi-access=free}}{{Cite journal|last1=Clyde|first1=Karen|last2=Barrera|first2=Julio|last3=Harris|first3=Eva|date=2008-09-01|title=The capsid-coding region hairpin element (cHP) is a critical determinant of dengue virus and West Nile virus RNA synthesis|journal=Virology|language=en|volume=379|issue=2|pages=314–323|doi=10.1016/j.virol.2008.06.034|pmc=2628549|pmid=18676000}}

The first structural element is termed 5'SLA and comprises three stems (S1, S2, S3) folded as L-shaped-like stem structure,{{Cite journal|last1=Lee|first1=Eunhye|last2=Bujalowski|first2=Paul J.|last3=Teramoto|first3=Tadahisa|last4=Gottipati|first4=Keerthi|last5=Scott|first5=Seth D.|last6=Padmanabhan|first6=Radhakrishnan|last7=Choi|first7=Kyung H.|date=2021-05-05|title=Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase|journal=Nature Communications|language=en|volume=12|issue=1|pages=2530|doi=10.1038/s41467-021-22846-1|pmid=33953197|issn=2041-1723|pmc=8100141|bibcode=2021NatCo..12.2530L}} and a side structure domain (SSD). Its overall length is around 70 nucleotides. Disruption experiments of S1 and S2 led to a stop of viral replication. Further, SLA is the promoter for RNA synthesis and interacts with the viral protein NS5 during circularization of the viral genome.{{Cite journal|last=Filomatori|first=C. V.|date=2006-08-15|title=A 5' RNA element promotes dengue virus RNA synthesis on a circular genome|journal=Genes & Development|language=en|volume=20|issue=16|pages=2238–2249|doi=10.1101/gad.1444206|issn=0890-9369|pmc=1553207|pmid=16882970}}{{Cite journal|last1=Yu|first1=Li|last2=Nomaguchi|first2=Masako|last3=Padmanabhan|first3=R.|last4=Markoff|first4=Lewis|date=2008-04-01|title=Specific requirements for elements of the 5′ and 3′ terminal regions in flavivirus RNA synthesis and viral replication|journal=Virology|language=en|volume=374|issue=1|pages=170–185|doi=10.1016/j.virol.2007.12.035|pmc=3368002|pmid=18234265}} After recruitment of NS5, the two loop regions of S3 (TL) and SSD (SSL) are considered to interact with NS5 to promote polymerase activity.{{Cite journal|last1=Filomatori|first1=Claudia V.|last2=Iglesias|first2=Nestor G.|last3=Villordo|first3=Sergio M.|last4=Alvarez|first4=Diego E.|last5=Gamarnik|first5=Andrea V.|date=2011-03-04|title=RNA Sequences and Structures Required for the Recruitment and Activity of the Dengue Virus Polymerase|journal=Journal of Biological Chemistry|language=en|volume=286|issue=9|pages=6929–6939|doi=10.1074/jbc.M110.162289|issn=0021-9258|pmc=3044948|pmid=21183683|doi-access=free}} Despite the diversity of SSD, its stable structure is essential for infectivity.

The second element is termed 5'SLB and contains the translation initiation codon at the top region of the stem loop. It further contains the 5'UAR (upstream AUG region), which is essential for the circularization of the genome.{{Cite journal|last1=Alvarez|first1=Diego E.|last2=Lodeiro|first2=María F.|last3=Ludueña|first3=Silvio J.|last4=Pietrasanta|first4=Lía I.|last5=Gamarnik|first5=Andrea V.|date=2005-06-01|title=Long-Range RNA-RNA Interactions Circularize the Dengue Virus Genome|journal=Journal of Virology|language=en|volume=79|issue=11|pages=6631–6643|doi=10.1128/JVI.79.11.6631-6643.2005|issn=0022-538X|pmc=1112138|pmid=15890901}} The 5'UAR interacts with the 3'UAR, which is located at the 3' UTR of the genome to form a long-range RNA-RNA interaction.

The capsid-coding hairpin region (cHP) actually lies in the ORF of the viral genome and is followed by the 5'CS (conserved sequence), which forms another long-range RNA-RNA interaction with the 3' UTR (3'CS). The cHP aids in the start codon recognition and viral replication. Studies show that the function of cHP is sequence-independent but structure-dependent.{{Cite journal|last1=Clyde|first1=Karen|last2=Harris|first2=Eva|date=2006-03-01|title=RNA Secondary Structure in the Coding Region of Dengue Virus Type 2 Directs Translation Start Codon Selection and Is Required for Viral Replication|journal=Journal of Virology|language=en|volume=80|issue=5|pages=2170–2182|doi=10.1128/JVI.80.5.2170-2182.2006|issn=0022-538X|pmc=1395379|pmid=16474125}}

Category:Non-coding RNA

Category:Flaviviridae

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