We thank the members of the RR, SAT, and EKF labs for providing scientific discussion and constructive input. The abstract section of this manuscript was presented in the form of an abstract at the 49th International Herpesvirus Workshop and is included in the conference abstract collection (https://ksvirus.org/wp-content/uploads/2021/06/KSHV-2021-Abstract-Book_v1.pdf).
The authors declare that they have no conflicts of interest.
Ethical approval
Not applicable.
Consent to participate
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Consent to publication
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Availability of data and materials
RNA-seq datasets have been submitted to NCBI Gene Expression Omnibus (GEO) and can be accessed under GSE293213.
Funding
This work was supported by National Institutes of Health grant [P01CA214091-07] (RR, SAT, and EKF), National Institutes of Health grant supplement [P01CA214091-07S1] (ST), and UF Informatics Institute Fellowship [00130153] (DS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.
References
Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, et al. Identification of Herpesvirus-Like DNA Sequences in AIDS-Sssociated Kaposi’s Sarcoma.Science. 1994;266:1865–9. [DOI] [PubMed]
Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D, Babinet P, et al. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease.Blood. 1995;86:1276–80. [PubMed]
Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi’s Sarcoma–Associated Herpesvirus-Like DNA Sequences in AIDS-Related Body-Cavity–Based Lymphomas.N Engl J Med. 1995;332:1186–91. [DOI] [PubMed]
Russo JJ, Bohenzky RA, Chien MC, Chen J, Yan M, Maddalena D, et al. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8).Proc Natl Acad Sci U S A. 1996;93:14862–7. [DOI] [PubMed] [PMC]
Pfeffer S, Sewer A, Lagos-Quintana M, Sheridan R, Sander C, Grässer FA, et al. Identification of microRNAs of the herpesvirus family.Nat Methods. 2005;2:269–76. [DOI] [PubMed]
Samols MA, Hu J, Skalsky RL, Renne R. Cloning and Identification of a MicroRNA Cluster within the Latency-Associated Region of Kaposi's Sarcoma-Associated Herpesvirus.J Virol. 2005;79:9301–5. [DOI] [PubMed] [PMC]
Cai X, Cullen BR. Transcriptional Origin of Kaposi’s Sarcoma-Associated Herpesvirus MicroRNAs.J Virol. 2006;80:2234–42. [DOI] [PubMed] [PMC]
Grundhoff A, Sullivan CS, Ganem D. A combined computational and microarray-based approach identifies novel microRNAs encoded by human gamma-herpesviruses.RNA. 2006;12:733–50. [DOI] [PubMed] [PMC]
Sun R, Lin SF, Gradoville L, Miller G. Polyadenylylated nuclear RNA encoded by Kaposi sarcoma-associated herpesvirus.Proc Natl Acad Sci U S A. 1996;93:11883–8. [DOI] [PubMed] [PMC]
Chandriani S, Xu Y, Ganem D. The Lytic Transcriptome of Kaposi's Sarcoma-Associated Herpesvirus Reveals Extensive Transcription of Noncoding Regions, Including Regions Antisense to Important Genes.J Virol. 2010;84:7934–42. [DOI] [PubMed] [PMC]
Campbell M, Izumiya Y. PAN RNA: transcriptional exhaust from a viral engine.J Biomed Sci. 2020;27:41. [DOI] [PubMed] [PMC]
Gay LA, Stribling D, Turner PC, Renne R. Kaposi’s Sarcoma-Associated Herpesvirus MicroRNA Mutants Modulate Cancer Hallmark Phenotypic Differences in Human Endothelial Cells.J Virol. 2021;95:e02022–20. [DOI] [PubMed] [PMC]
Salzman J, Gawad C, Wang PL, Lacayo N, Brown PO. Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types.PLoS One. 2012;7:e30733. [DOI] [PubMed] [PMC]
Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, et al. Natural RNA circles function as efficient microRNA sponges.Nature. 2013;495:384–8. [DOI] [PubMed]
Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency.Nature. 2013;495:333–8. [DOI] [PubMed]
Li Z, Huang C, Bao C, Chen L, Lin M, Wang X, et al. Exon-intron circular RNAs regulate transcription in the nucleus.Nat Struct Mol Biol. 2015;22:256–64. [DOI] [PubMed]
Conn SJ, Pillman KA, Toubia J, Conn VM, Salmanidis M, Phillips CA, et al. The RNA Binding Protein Quaking Regulates Formation of circRNAs.Cell. 2015;160:1125–34. [DOI] [PubMed]
Du WW, Yang W, Liu E, Yang Z, Dhaliwal P, Yang BB. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2.Nucleic Acids Res. 2016;44:2846–58. [DOI] [PubMed] [PMC]
Liu CX, Li X, Nan F, Jiang S, Gao X, Guo SK, et al. Structure and Degradation of Circular RNAs Regulate PKR Activation in Innate Immunity.Cell. 2019;177:865–80.e21. [DOI] [PubMed]
Kleaveland B, Shi CY, Stefano J, Bartel DP. A Network of Noncoding Regulatory RNAs Acts in the Mammalian Brain.Cell. 2018;174:350–62.e17. [DOI] [PubMed] [PMC]
Legnini I, Di Timoteo G, Rossi F, Morlando M, Briganti F, Sthandier O, et al. Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis.Mol Cell. 2017;66:22–37.e9. [DOI] [PubMed] [PMC]
Ungerleider N, Concha M, Lin Z, Roberts C, Wang X, Cao S, et al. The Epstein Barr virus circRNAome.PLoS Pathog. 2018;14:e1007206. [DOI] [PubMed] [PMC]
Toptan T, Abere B, Nalesnik MA, Swerdlow SH, Ranganathan S, Lee N, et al. Circular DNA tumor viruses make circular RNAs.Proc Natl Acad Sci U S A. 2018;115:E8737–45. [DOI] [PubMed] [PMC]
Tagawa T, Gao S, Koparde VN, Gonzalez M, Spouge JL, Serquiña AP, et al. Discovery of Kaposi’s sarcoma herpesvirus-encoded circular RNAs and a human antiviral circular RNA.Proc Natl Acad Sci U S A. 2018;115:12805–10. [DOI] [PubMed] [PMC]
Ungerleider NA, Jain V, Wang Y, Maness NJ, Blair RV, Alvarez X, et al. Comparative Analysis of Gammaherpesvirus Circular RNA Repertoires: Conserved and Unique Viral Circular RNAs.J Virol. 2019;93:e01952–18. [DOI] [PubMed] [PMC]
Abere B, Li J, Zhou H, Toptan T, Moore PS, Chang Y. Kaposi’s Sarcoma-Associated Herpesvirus-Encoded circRNAs Are Expressed in Infected Tumor Tissues and Are Incorporated into Virions.mBio. 2020;11:e03027–19. [DOI] [PubMed] [PMC]
Yang C, Yuan W, Yang X, Li P, Wang J, Han J, et al. Circular RNA circ-ITCH inhibits bladder cancer progression by sponging miR-17/miR-224 and regulating p21, PTEN expression.Mol Cancer. 2018;17:19. [DOI] [PubMed] [PMC]
Liang WC, Wong CW, Liang PP, Shi M, Cao Y, Rao ST, et al. Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway.Genome Biol. 2019;20:84. [DOI] [PubMed] [PMC]
Zou Y, Yang A, Chen B, Deng X, Xie J, Dai D, et al. crVDAC3 alleviates ferroptosis by impeding HSPB1 ubiquitination and confers trastuzumab deruxtecan resistance in HER2-low breast cancer.Drug Resist Updat. 2024;77:101126. [DOI] [PubMed]
Tagawa T, Oh D, Dremel S, Mahesh G, Koparde VN, Duncan G, et al. A virus-induced circular RNA maintains latent infection of Kaposi’s sarcoma herpesvirus.Proc Natl Acad Sci U S A. 2023;120:e2212864120. [DOI] [PubMed] [PMC]
Brulois KF, Chang H, Lee AS, Ensser A, Wong LY, Toth Z, et al. Construction and Manipulation of a New Kaposi’s Sarcoma-Associated Herpesvirus Bacterial Artificial Chromosome Clone.J Virol. 2012;86:9708–20. [DOI] [PubMed] [PMC]
Elizarraras JM, Liao Y, Shi Z, Zhu Q, Pico AR, Zhang B. WebGestalt 2024: faster gene set analysis and new support for metabolomics and multi-omics.Nucleic Acids Res. 2024;52:W415–21. [DOI] [PubMed] [PMC]
Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs.Nat Rev Genet. 2019;20:675–91. [DOI] [PubMed]
Ottesen EW, Luo D, Seo J, Singh NN, Singh RN. Human Survival Motor Neuron genes generate a vast repertoire of circular RNAs.Nucleic Acids Res. 2019;47:2884–905. [DOI] [PubMed] [PMC]
Zhang XO, Dong R, Zhang Y, Zhang JL, Luo Z, Zhang J, et al. Diverse alternative back-splicing and alternative splicing landscape of circular RNAs.Genome Res. 2016;26:1277–87. [DOI] [PubMed] [PMC]
Rahman FA, Krause MP. PAI-1, the Plasminogen System, and Skeletal Muscle.Int J Mol Sci. 2020;21:7066. [DOI] [PubMed] [PMC]
Dellas C, Loskutoff DJ. Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease.Thromb Haemost. 2005;93:631–40. [DOI] [PubMed]
Dittmann M, Hoffmann HH, Scull MA, Gilmore RH, Bell KL, Ciancanelli M, et al. A Serpin Shapes the Extracellular Environment to Prevent Influenza A Virus Maturation.Cell. 2015;160:631–43. [DOI] [PubMed] [PMC]
Vozza A, Parisi G, De Leonardis F, Lasorsa FM, Castegna A, Amorese D, et al. UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation.Proc Natl Acad Sci U S A. 2014;111:960–5. [DOI] [PubMed] [PMC]
Luby A, Alves-Guerra MC. UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control.Int J Mol Sci. 2022;23:15077. [DOI] [PubMed] [PMC]
Liu SJ, Dang HX, Lim DA, Feng FY, Maher CA. Long noncoding RNAs in cancer metastasis.Nat Rev Cancer. 2021;21:446–60. [DOI] [PubMed] [PMC]
Pickard MR, Williams GT. Molecular and Cellular Mechanisms of Action of Tumour Suppressor GAS5 LncRNA.Genes (Basel). 2015;6:484–99. [DOI] [PubMed] [PMC]
Gutschner T, Hämmerle M, Eissmann M, Hsu J, Kim Y, Hung G, et al. The Noncoding RNA MALAT1 Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells.Cancer Res. 2013;73:1180–9. [DOI] [PubMed] [PMC]
Sethuraman S, Thomas M, Gay LA, Renne R. Computational analysis of ribonomics datasets identifies long non-coding RNA targets of γ-herpesviral miRNAs.Nucleic Acids Res. 2018;46:8574–89. [DOI] [PubMed] [PMC]
Shao T, Pan YH, Xiong XD. Circular RNA: an important player with multiple facets to regulate its parental gene expression.Mol Ther Nucleic Acids. 2020;23:369–76. [DOI] [PubMed] [PMC]
Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O, Hanan M, et al. circRNA Biogenesis Competes with Pre-mRNA Splicing.Mol Cell. 2014;56:55–66. [DOI] [PubMed]
Majerciak V, Alvarado-Hernandez B, Lobanov A, Cam M, Zheng ZM. Genome-wide regulation of KSHV RNA splicing by viral RNA-binding protein ORF57.PLoS Pathog. 2022;18:e1010311. [DOI] [PubMed] [PMC]
Tagawa T, Oh D, Santos J, Dremel S, Mahesh G, Uldrick TS, et al. Characterizing Expression and Regulation of Gamma-Herpesviral Circular RNAs.Front Microbiol. 2021;12:670542. [DOI] [PubMed] [PMC]
Xie J, Ye F, Deng X, Tang Y, Liang JY, Huang X, et al. Circular RNA: A promising new star of vaccine.J Transl Int Med. 2023;11:372–81. [DOI] [PubMed] [PMC]
O’Leary E, Jiang Y, Kristensen LS, Hansen TB, Kjems J. The therapeutic potential of circular RNAs.Nat Rev Genet. 2025;26:230–44. [DOI] [PubMed]
Gong LP, Chen JN, Dong M, Xiao ZD, Feng ZY, Pan YH, et al. Epstein-Barr virus-derived circular RNA LMP2A induces stemness in EBV-associated gastric cancer.EMBO Rep. 2020;21:e49689. [DOI] [PubMed] [PMC]
Ge J, Wang J, Xiong F, Jiang X, Zhu K, Wang Y, et al. Epstein-Barr Virus-Encoded Circular RNA CircBART2.2 Promotes Immune Escape of Nasopharyngeal Carcinoma by Regulating PD-L1.Cancer Res. 2021;81:5074–88. [DOI] [PubMed] [PMC]