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Structure-first identification of RNA elements that regulate dengue virus genome architecture and replication
The genomes of RNA viruses encode the information required for replication in host cells both in their linear sequence and in complex higher-order structures. A subset of these RNA genome structures show clear sequence conservation, and have been extensively described for well-characterized viruses....
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Published in: | Proceedings of the National Academy of Sciences - PNAS 2023-04, Vol.120 (15), p.e2217053120-e2217053120 |
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creator | Boerneke, Mark A Gokhale, Nandan S Horner, Stacy M Weeks, Kevin M |
description | The genomes of RNA viruses encode the information required for replication in host cells both in their linear sequence and in complex higher-order structures. A subset of these RNA genome structures show clear sequence conservation, and have been extensively described for well-characterized viruses. However, the extent to which viral RNA genomes contain functional structural elements-unable to be detected by sequence alone-that nonetheless are critical to viral fitness is largely unknown. Here, we devise a structure-first experimental strategy and use it to identify 22 structure-similar motifs across the coding sequences of the RNA genomes for the four dengue virus serotypes. At least 10 of these motifs modulate viral fitness, revealing a significant unnoticed extent of RNA structure-mediated regulation within viral coding sequences. These viral RNA structures promote a compact global genome architecture, interact with proteins, and regulate the viral replication cycle. These motifs are also thus constrained at the levels of both RNA structure and protein sequence and are potential resistance-refractory targets for antivirals and live-attenuated vaccines. Structure-first identification of conserved RNA structure enables efficient discovery of pervasive RNA-mediated regulation in viral genomes and, likely, other cellular RNAs. |
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A subset of these RNA genome structures show clear sequence conservation, and have been extensively described for well-characterized viruses. However, the extent to which viral RNA genomes contain functional structural elements-unable to be detected by sequence alone-that nonetheless are critical to viral fitness is largely unknown. Here, we devise a structure-first experimental strategy and use it to identify 22 structure-similar motifs across the coding sequences of the RNA genomes for the four dengue virus serotypes. At least 10 of these motifs modulate viral fitness, revealing a significant unnoticed extent of RNA structure-mediated regulation within viral coding sequences. These viral RNA structures promote a compact global genome architecture, interact with proteins, and regulate the viral replication cycle. These motifs are also thus constrained at the levels of both RNA structure and protein sequence and are potential resistance-refractory targets for antivirals and live-attenuated vaccines. Structure-first identification of conserved RNA structure enables efficient discovery of pervasive RNA-mediated regulation in viral genomes and, likely, other cellular RNAs.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2217053120</identifier><identifier>PMID: 37011200</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Amino acid sequence ; Antiviral agents ; Biological Sciences ; Conserved sequence ; Dengue ; Dengue fever ; Fitness ; Gene sequencing ; Genome, Viral - genetics ; Genomes ; Humans ; Nucleic Acid Conformation ; Nucleotide sequence ; Protein structure ; Proteins ; Replication ; RNA viruses ; RNA Viruses - genetics ; RNA, Viral - metabolism ; Serotypes ; Structural members ; Structure-function relationships ; Vaccines ; Vector-borne diseases ; Virus Replication - genetics ; Viruses</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2023-04, Vol.120 (15), p.e2217053120-e2217053120</ispartof><rights>Copyright National Academy of Sciences Apr 11, 2023</rights><rights>Copyright © 2023 the Author(s). Published by PNAS. 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-569616b3a8b04eb1d0315b683b2235ec33bacb986ce9b1378115c2bb1a3c864c3</citedby><cites>FETCH-LOGICAL-c422t-569616b3a8b04eb1d0315b683b2235ec33bacb986ce9b1378115c2bb1a3c864c3</cites><orcidid>0000-0003-0092-3203 ; 0000-0002-6748-9985 ; 0000-0002-9351-7409</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104495/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104495/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37011200$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Boerneke, Mark A</creatorcontrib><creatorcontrib>Gokhale, Nandan S</creatorcontrib><creatorcontrib>Horner, Stacy M</creatorcontrib><creatorcontrib>Weeks, Kevin M</creatorcontrib><title>Structure-first identification of RNA elements that regulate dengue virus genome architecture and replication</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The genomes of RNA viruses encode the information required for replication in host cells both in their linear sequence and in complex higher-order structures. A subset of these RNA genome structures show clear sequence conservation, and have been extensively described for well-characterized viruses. However, the extent to which viral RNA genomes contain functional structural elements-unable to be detected by sequence alone-that nonetheless are critical to viral fitness is largely unknown. Here, we devise a structure-first experimental strategy and use it to identify 22 structure-similar motifs across the coding sequences of the RNA genomes for the four dengue virus serotypes. At least 10 of these motifs modulate viral fitness, revealing a significant unnoticed extent of RNA structure-mediated regulation within viral coding sequences. These viral RNA structures promote a compact global genome architecture, interact with proteins, and regulate the viral replication cycle. These motifs are also thus constrained at the levels of both RNA structure and protein sequence and are potential resistance-refractory targets for antivirals and live-attenuated vaccines. Structure-first identification of conserved RNA structure enables efficient discovery of pervasive RNA-mediated regulation in viral genomes and, likely, other cellular RNAs.</description><subject>Amino acid sequence</subject><subject>Antiviral agents</subject><subject>Biological Sciences</subject><subject>Conserved sequence</subject><subject>Dengue</subject><subject>Dengue fever</subject><subject>Fitness</subject><subject>Gene sequencing</subject><subject>Genome, Viral - genetics</subject><subject>Genomes</subject><subject>Humans</subject><subject>Nucleic Acid Conformation</subject><subject>Nucleotide sequence</subject><subject>Protein structure</subject><subject>Proteins</subject><subject>Replication</subject><subject>RNA viruses</subject><subject>RNA Viruses - genetics</subject><subject>RNA, Viral - metabolism</subject><subject>Serotypes</subject><subject>Structural members</subject><subject>Structure-function relationships</subject><subject>Vaccines</subject><subject>Vector-borne diseases</subject><subject>Virus Replication - genetics</subject><subject>Viruses</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNpdkcuLFDEQh4Mo7rh69iYBL156t_LodPoky-ILFgUf55BkqmeydHfGPBb878264_o4FVR99VHFj5DnDM4YDOL8sNp8xjkboBeMwwOyYTCyTskRHpINAB86Lbk8IU9yvgaAsdfwmJyIAVjDYUOWLyVVX2rCbgopFxq2uJYwBW9LiCuNE_388YLijEvrZ1r2ttCEuzrbgrSxu4r0JqSa6Q7XuCC1ye9DwV9Oatdtow_zUfeUPJrsnPHZsZ6Sb2_ffL183119evfh8uKq85Lz0vVqVEw5YbUDiY5tQbDeKS0c56JHL4Sz3o1aeRwdE4NmrPfcOWaF10p6cUpe33kP1S249e30ZGdzSGGx6YeJNph_J2vYm128MQwYSDn2zfDqaEjxe8VczBKyx3m2K8aaDR8apIDLsaEv_0OvY01r-89wDRw0BzU06vyO8inmnHC6v4aBuc3S3GZp_mTZNl78_cQ9_zs88RNC-Zyt</recordid><startdate>20230411</startdate><enddate>20230411</enddate><creator>Boerneke, Mark A</creator><creator>Gokhale, Nandan S</creator><creator>Horner, Stacy M</creator><creator>Weeks, Kevin M</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0092-3203</orcidid><orcidid>https://orcid.org/0000-0002-6748-9985</orcidid><orcidid>https://orcid.org/0000-0002-9351-7409</orcidid></search><sort><creationdate>20230411</creationdate><title>Structure-first identification of RNA elements that regulate dengue virus genome architecture and replication</title><author>Boerneke, Mark A ; Gokhale, Nandan S ; Horner, Stacy M ; Weeks, Kevin M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-569616b3a8b04eb1d0315b683b2235ec33bacb986ce9b1378115c2bb1a3c864c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Amino acid sequence</topic><topic>Antiviral agents</topic><topic>Biological Sciences</topic><topic>Conserved sequence</topic><topic>Dengue</topic><topic>Dengue fever</topic><topic>Fitness</topic><topic>Gene sequencing</topic><topic>Genome, Viral - genetics</topic><topic>Genomes</topic><topic>Humans</topic><topic>Nucleic Acid Conformation</topic><topic>Nucleotide sequence</topic><topic>Protein structure</topic><topic>Proteins</topic><topic>Replication</topic><topic>RNA viruses</topic><topic>RNA Viruses - genetics</topic><topic>RNA, Viral - metabolism</topic><topic>Serotypes</topic><topic>Structural members</topic><topic>Structure-function relationships</topic><topic>Vaccines</topic><topic>Vector-borne diseases</topic><topic>Virus Replication - genetics</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Boerneke, Mark A</creatorcontrib><creatorcontrib>Gokhale, Nandan S</creatorcontrib><creatorcontrib>Horner, Stacy M</creatorcontrib><creatorcontrib>Weeks, Kevin M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Boerneke, Mark A</au><au>Gokhale, Nandan S</au><au>Horner, Stacy M</au><au>Weeks, Kevin M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-first identification of RNA elements that regulate dengue virus genome architecture and replication</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2023-04-11</date><risdate>2023</risdate><volume>120</volume><issue>15</issue><spage>e2217053120</spage><epage>e2217053120</epage><pages>e2217053120-e2217053120</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Edited by Juli Feigon, University of California, Los Angeles, CA; received October 5, 2022; accepted March 2, 2023</notes><abstract>The genomes of RNA viruses encode the information required for replication in host cells both in their linear sequence and in complex higher-order structures. A subset of these RNA genome structures show clear sequence conservation, and have been extensively described for well-characterized viruses. However, the extent to which viral RNA genomes contain functional structural elements-unable to be detected by sequence alone-that nonetheless are critical to viral fitness is largely unknown. Here, we devise a structure-first experimental strategy and use it to identify 22 structure-similar motifs across the coding sequences of the RNA genomes for the four dengue virus serotypes. At least 10 of these motifs modulate viral fitness, revealing a significant unnoticed extent of RNA structure-mediated regulation within viral coding sequences. These viral RNA structures promote a compact global genome architecture, interact with proteins, and regulate the viral replication cycle. These motifs are also thus constrained at the levels of both RNA structure and protein sequence and are potential resistance-refractory targets for antivirals and live-attenuated vaccines. Structure-first identification of conserved RNA structure enables efficient discovery of pervasive RNA-mediated regulation in viral genomes and, likely, other cellular RNAs.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>37011200</pmid><doi>10.1073/pnas.2217053120</doi><orcidid>https://orcid.org/0000-0003-0092-3203</orcidid><orcidid>https://orcid.org/0000-0002-6748-9985</orcidid><orcidid>https://orcid.org/0000-0002-9351-7409</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Amino acid sequence Antiviral agents Biological Sciences Conserved sequence Dengue Dengue fever Fitness Gene sequencing Genome, Viral - genetics Genomes Humans Nucleic Acid Conformation Nucleotide sequence Protein structure Proteins Replication RNA viruses RNA Viruses - genetics RNA, Viral - metabolism Serotypes Structural members Structure-function relationships Vaccines Vector-borne diseases Virus Replication - genetics Viruses |
title | Structure-first identification of RNA elements that regulate dengue virus genome architecture and replication |
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