Editing Flavivirus (section)

==RNA secondary structure elements==
[[File:Fgene-09-00595-g001.jpg|thumb|''Flavivirus'' RNA genome showing the 3' and 5' UTRs and cyclisation]]

The positive sense RNA genome of ''Flavivirus'' contains 5' and 3' [[untranslated region]]s (UTRs).

===5'UTR===
{{main|Flavivirus 5' UTR}}

The 5'UTRs are 95–101 nucleotides long in [[Dengue virus]].<ref name="pmid21994804">{{cite journal|vauthors=Gebhard LG, Filomatori CV, Gamarnik AV | title=Functional RNA elements in the dengue virus genome | journal=Viruses | year= 2011 | volume= 3 | issue= 9 | pages= 1739–56 | pmid=21994804 | doi=10.3390/v3091739 | pmc=3187688 | doi-access=free }}</ref> There are two conserved structural elements in the ''Flavivirus'' 5'UTR, a large stem loop (SLA) and a short stem loop (SLB). SLA folds into a Y-shaped structure with a side stem loop and a small top loop.<ref name="pmid21994804" /><ref name="pmid2829420">{{cite journal|vauthors=Brinton MA, Dispoto JH | title=Sequence and secondary structure analysis of the 5'-terminal region of flavivirus genome RNA | journal=Virology | year= 1988 | volume= 162 | issue= 2 | pages= 290–9 | doi= 10.1016/0042-6822(88)90468-0| pmid=2829420  }}</ref> SLA is likely to act as a promoter, and is essential for viral RNA synthesis.<ref name="pmid16882970">{{cite journal|vauthors=Filomatori CV, Lodeiro MF, Alvarez DE, Samsa MM, Pietrasanta L, Gamarnik AV | title=A 5' RNA element promotes dengue virus RNA synthesis on a circular genome | journal=Genes Dev | year= 2006 | volume= 20 | issue= 16 | pages= 2238–49 | pmid=16882970 | doi=10.1101/gad.1444206 | pmc=1553207 }}</ref><ref name="pmid18234265">{{cite journal|vauthors=Yu L, Nomaguchi M, Padmanabhan R, Markoff L | title=Specific requirements for elements of the 5' and 3' terminal regions in flavivirus RNA synthesis and viral replication | journal=Virology | year= 2008 | volume= 374 | issue= 1 | pages= 170–85 | pmid=18234265 | doi=10.1016/j.virol.2007.12.035 | pmc=3368002 }}</ref> SLB is involved in interactions between the 5'UTR and 3'UTR which result in the cyclisation of the viral RNA, which is essential for viral replication.<ref name="pmid15890901">{{cite journal|vauthors=Alvarez DE, Lodeiro MF, Ludueña SJ, Pietrasanta LI, Gamarnik AV | title=Long-range RNA-RNA interactions circularize the dengue virus genome | journal=J Virol | year= 2005 | volume= 79 | issue= 11 | pages= 6631–43 | pmid=15890901 | doi=10.1128/JVI.79.11.6631-6643.2005 | pmc=1112138 }}</ref>

===3'UTR===
{{main|Flavivirus 3' UTR}}
[[File:Viruses-11-00298-g002.webp|thumb|RNA secondary structure elements of different flavivirus 3′UTRs]]
The 3'UTRs are typically 0.3–0.5&nbsp;kb in length and contain a number of highly conserved [[secondary structure]]s which are conserved and restricted to flaviviruses. The majority of analysis has been carried out using [[West Nile virus]] (WNV) to study the function the 3'UTR.{{cn|date=October 2022}}

Currently 8 secondary structures have been identified within the 3'UTR of WNV and are (in the order in which they are found with the 3'UTR)  SL-I, SL-II, SL-III, SL-IV, DB1, DB2 and CRE.<ref name="pmid15956576">{{cite journal |vauthors=Chiu WW, Kinney RM, Dreher TW |title=Control of Translation by the 5′- and 3′-Terminal Regions of the Dengue Virus Genome |journal=J. Virol. |volume=79 |issue=13 |pages=8303–15 |date=July 2005 |pmid=15956576 |pmc=1143759 |doi=10.1128/JVI.79.13.8303-8315.2005 }}</ref><ref name="pmid19064258">{{cite journal |vauthors=Pijlman GP, Funk A, Kondratieva N |title=A highly structured, nuclease-resistant, noncoding RNA produced by flaviviruses is required for pathogenicity |journal=Cell Host Microbe |volume=4 |issue=6 |pages=579–91 |date=December 2008 |pmid=19064258 |doi=10.1016/j.chom.2008.10.007 |display-authors=etal|doi-access=free }}</ref> Some of these secondary structures have been characterised and are important in facilitating [[viral replication]] and protecting the 3'UTR from 5' [[endonuclease]] digestion. Nuclease resistance protects the downstream 3' UTR RNA fragment from degradation and is essential for virus-induced cytopathicity and pathogenicity.{{cn|date=October 2022}}
* '''SL-II'''

SL-II has been suggested to contribute to nuclease resistance.<ref name="pmid19064258"/> It may be related to another [[hairpin loop]] identified in the 5'UTR of the [[Japanese encephalitis virus]] (JEV) genome.<ref name="pmid15113895">{{cite journal |vauthors=Lin KC, Chang HL, Chang RY |title=Accumulation of a 3′-Terminal Genome Fragment in Japanese Encephalitis Virus-Infected Mammalian and Mosquito Cells |journal=J. Virol. |volume=78 |issue=10 |pages=5133–8 |date=May 2004 |pmid=15113895 |pmc=400339 |doi= 10.1128/JVI.78.10.5133-5138.2004}}</ref> The JEV hairpin is significantly over-represented upon host cell infection and it has been suggested that the hairpin structure may play a role in regulating RNA synthesis.{{cn|date=October 2022}}
* '''SL-IV'''

This secondary structure is located within the 3'UTR of the genome of ''Flavivirus'' upstream of the DB elements. The function of this conserved structure is unknown but is thought to contribute to ribonuclease resistance.{{cn|date=October 2022}}
* '''DB1/DB2'''
[[File:RF00525.png|thumb|Secondary structure of the ''Flavivirus'' DB element|upright]]These two conserved secondary structures are also known as pseudo-repeat elements. They were originally identified within the genome of Dengue virus and are found adjacent to each other within the 3'UTR. They appear to be widely conserved across the Flaviviradae. These DB elements have a secondary structure consisting of three helices and they play a role in ensuring efficient translation. Deletion of DB1 has a small but significant reduction in translation but deletion of DB2 has little effect. Deleting both DB1 and DB2 reduced [[translation (biology)|translation]] efficiency of the viral genome to 25%.<ref name="pmid15956576"/>
* '''CRE'''

CRE is the Cis-acting replication element, also known as the 3'SL RNA elements, and is thought to be essential in viral replication by facilitating the formation of a "replication complex".<ref name="pmid9696848">{{cite journal |vauthors=Zeng L, Falgout B, Markoff L |title=Identification of Specific Nucleotide Sequences within the Conserved 3′-SL in the Dengue Type 2 Virus Genome Required for Replication |journal=J. Virol. |volume=72 |issue=9 |pages=7510–22 |date=September 1998 |pmid=9696848 |pmc=109990 |doi= 10.1128/JVI.72.9.7510-7522.1998}}</ref> Although evidence has been presented for an existence of a [[pseudoknot]] structure in this RNA, it does not appear to be well conserved across flaviviruses.<ref name="pmid8672458">{{cite journal |vauthors=Shi PY, Brinton MA, Veal JM, Zhong YY, Wilson WD |title=Evidence for the existence of a pseudoknot structure at the 3' terminus of the flavivirus genomic RNA |journal=Biochemistry |volume=35 |issue=13 |pages=4222–30 |date=April 1996 |pmid=8672458 |doi=10.1021/bi952398v }}</ref> Deletions of the 3' UTR of flaviviruses have been shown to be lethal for infectious clones.

===Conserved hairpin cHP===
A [[Flavivirus capsid hairpin cHP|conserved hairpin (cHP)]] structure was later found in several ''Flavivirus'' [[genome]]s and is thought to direct translation of capsid proteins. It is located just downstream of the AUG [[start codon]].<ref>{{cite journal |author1= Clyde K, Harris E |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= J Virol |volume= 80 |issue=  5|pages= 2170–2182 |year= 2006 |pmid=16474125 |doi= 10.1128/JVI.80.5.2170-2182.2006 |pmc= 1395379}}</ref>