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Annual Review of Cell and Developmental Biology

Volume 38, 2022

Biogenesis and Regulatory Roles of Circular RNAs

Abstract

Covalently closed, single-stranded circular RNAs can be produced from viral RNA genomes as well as from the processing of cellular housekeeping noncoding RNAs and precursor messenger RNAs. Recent transcriptomic studies have surprisingly uncovered that many protein-coding genes can be subjected to backsplicing, leading to widespread expression of a specific type of circular RNAs (circRNAs) in eukaryotic cells. Here, we discuss experimental strategies used to discover and characterize diverse circRNAs at both the genome and individual gene scales. We further highlight the current understanding of how circRNAs are generated and how the mature transcripts function. Some circRNAs act as noncoding RNAs to impact gene regulation by serving as decoys or competitors for microRNAs and proteins. Others form extensive networks of ribonucleoprotein complexes or encode functional peptides that are translated in response to certain cellular stresses. Overall, circRNAs have emerged as an important class of RNAmolecules in gene expression regulation that impact many physiological processes, including early development, immune responses, neurogenesis, and tumorigenesis.

Keyword(s): backsplicing, circRNA, microRNA, noncoding RNA, pre-mRNA splicing, translation
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/content/journals/10.1146/annurev-cellbio-120420-125117
2022-10-06
2024-04-18
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Literature Cited

  1. Ai Y, Liang D, Wilusz JE. 2022. CRISPR/Cas13 effectors have differing extents of off-target effects that limit their utility in eukaryotic cells. Nucleic Acids Res 50e65
     [Google Scholar]
  2. Aktaş T, Avşar Ilik I, Maticzka D, Bhardwaj V, Pessoa Rodrigues C et al. 2017. DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome. Nature 544:115–19
     [Google Scholar]
  3. Arnberg AC, Van Ommen GJ, Grivell LA, Van Bruggen EF, Borst P. 1980. Some yeast mitochondrial RNAs are circular. Cell 19:313–19
     [Google Scholar]
  4. Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O et al. 2014. circRNA biogenesis competes with pre-mRNA splicing. Mol. Cell 56:55–66
     [Google Scholar]
  5. Bachmayr-Heyda A, Reiner AT, Auer K, Sukhbaatar N, Aust S et al. 2015. Correlation of circular RNA abundance with proliferation – exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis, and normal human tissues. Sci. Rep. 5:8057
     [Google Scholar]
  6. Bahn JH, Zhang Q, Li F, Chan T-M, Lin X et al. 2015. The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva. Clin. Chem. 61:221–30
     [Google Scholar]
  7. Barrett SP, Parker KR, Horn C, Mata M, Salzman J. 2017. ciRS-7 exonic sequence is embedded in a long non-coding RNA locus. PLOS Genet. 13:e1007114
     [Google Scholar]
  8. Barrett SP, Wang PL, Salzman J 2015. Circular RNA biogenesis can proceed through an exon-containing lariat precursor. eLife 4:e07540
     [Google Scholar]
  9. Bentley DL. 2014. Coupling mRNA processing with transcription in time and space. Nat. Rev. Genet. 15:163–75
     [Google Scholar]
  10. Bosson AD, Zamudio JR, Sharp PA. 2014. Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition. Mol. Cell 56:347–59
     [Google Scholar]
  11. Burd CE, Jeck WR, Liu Y, Sanoff HK, Wang Z, Sharpless NE 2010. Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk. PLOS Genet. 6:e1001233
     [Google Scholar]
  12. Burggraf S, Larsen N, Woese CR, Stetter KO. 1993. An intron within the 16S ribosomal RNA gene of the archaeon Pyrobaculum aerophilum. PNAS 90:2547–50
     [Google Scholar]
  13. Capel B, Swain A, Nicolis S, Hacker A, Walter M et al. 1993. Circular transcripts of the testis-determining gene Sry in adult mouse testis. Cell 73:1019–30
     [Google Scholar]
  14. Cech TR. 1990. Self-splicing of group I introns. Annu. Rev. Biochem. 59:543–68
     [Google Scholar]
  15. Chen C-K, Cheng R, Demeter J, Chen J, Weingarten-Gabbay S et al. 2021. Structured elements drive extensive circular RNA translation. Mol. Cell 81:4300–18.e13
     [Google Scholar]
  16. Chen C-Y, Sarnow P. 1995. Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. Science 268:415–17
     [Google Scholar]
  17. Chen L-L. 2016. The biogenesis and emerging roles of circular RNAs. Nat. Rev. Mol. Cell Biol. 17:205–11
     [Google Scholar]
  18. Chen L-L. 2020. The expanding regulatory mechanisms and cellular functions of circular RNAs. Nat. Rev. Mol. Cell Biol. 21:475–90
     [Google Scholar]
  19. Chen L-L, Yang L 2015. Regulation of circRNA biogenesis. RNA Biol 12:381–88
     [Google Scholar]
  20. Chen S, Huang V, Xu X, Livingstone J, Soares F et al. 2019. Widespread and functional RNA circularization in localized prostate cancer. Cell 176:831–43.e22
     [Google Scholar]
  21. Chen YG, Chen R, Ahmad S, Verma R, Kasturi SP et al. 2019. N6-methyladenosine modification controls circular RNA immunity. Mol. Cell 76:96–109.e9
     [Google Scholar]
  22. Chen YG, Kim MV, Chen X, Batista PJ, Aoyama S et al. 2017. Sensing self and foreign circular RNAs by intron identity. Mol. Cell 67:228–38.e5
     [Google Scholar]
  23. Chuang T-J, Chen Y-J, Chen C-Y, Mai T-L, Wang Y-D et al. 2018. Integrative transcriptome sequencing reveals extensive alternative trans-splicing and cis-backsplicing in human cells. Nucleic Acids Res. 46:3671–91
     [Google Scholar]
  24. Cloonan N, Forrest AR, Kolle G, Gardiner BB, Faulkner GJ et al. 2008. Stem cell transcriptome profiling via massive-scale mRNA sequencing. Nat. Methods 5:613–19
     [Google Scholar]
  25. Clouet d'Orval B, Bortolin M-L, Gaspin C, Bachellerie J-P. 2001. Box C/D RNA guides for the ribose methylation of archaeal tRNAs. The tRNATrp intron guides the formation of two ribose-methylated nucleosides in the mature tRNATrp. Nucleic Acids Res. 29:4518–29
     [Google Scholar]
  26. Cocquerelle C, Daubersies P, Majerus MA, Kerckaert JP, Bailleul B. 1992. Splicing with inverted order of exons occurs proximal to large introns. EMBO J. 11:1095–98
     [Google Scholar]
  27. Cocquerelle C, Mascrez B, Hetuin D, Bailleul B. 1993. Mis-splicing yields circular RNA molecules. FASEB J. 7:155–60
     [Google Scholar]
  28. Conn SJ, Pillman KA, Toubia J, Conn VM, Salmanidis M et al. 2015. The RNA binding protein Quaking regulates formation of circRNAs. Cell 160:1125–34
     [Google Scholar]
  29. Conn VM, Hugouvieux V, Nayak A, Conos SA, Capovilla G et al. 2017. A circRNA from SEPALLATA3 regulates splicing of its cognate mRNA through R-loop formation. Nat. Plants 3:17053
     [Google Scholar]
  30. Cortés-López M, Gruner MR, Cooper DA, Gruner HN, Voda AI et al. 2018. Global accumulation of circRNAs during aging in Caenorhabditis elegans. BMC Genom 19:8
     [Google Scholar]
  31. Côté F, Perreault J-P. 1997. Peach latent mosaic viroid is locked by a 2′,5′-phosphodiester bond produced by in vitro self-ligation. J. Mol. Biol. 273:533–43
     [Google Scholar]
  32. Dalgaard JZ, Garrett RA. 1992. Protein-coding introns from the 23S rRNA-encoding gene form stable circles in the hyperthermophilic archaeon Pyrobaculum organotrophum. Gene 121:103–10
     [Google Scholar]
  33. Danan M, Schwartz S, Edelheit S, Sorek R. 2012. Transcriptome-wide discovery of circular RNAs in Archaea. Nucleic Acids Res. 40:3131–42
     [Google Scholar]
  34. Denzler R, Agarwal V, Stefano J, Bartel DP, Stoffel M. 2014. Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. Mol. Cell 54:766–76
     [Google Scholar]
  35. Dodbele S, Mutlu N, Wilusz JE. 2021. Best practices to ensure robust investigation of circular RNAs: pitfalls and tips. EMBO Rep. 22:e52072
     [Google Scholar]
  36. Dong R, Ma X-K, Chen L-L, Yang L 2017. Increased complexity of circRNA expression during species evolution. RNA Biol 14:1064–74
     [Google Scholar]
  37. Dong R, Ma X-K, Li G-W, Yang L 2018. CIRCpedia v2: An updated database for comprehensive circular RNA annotation and expression comparison. Genom. Proteom. Bioinform. 16:226–33
     [Google Scholar]
  38. Du WW, Yang W, Liu E, Yang Z, Dhaliwal P, Yang BB. 2016. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res. 44:2846–58
     [Google Scholar]
  39. Dubin RA, Kazmi MA, Ostrer H. 1995. Inverted repeats are necessary for circularization of the mouse testis Sry transcript. Gene 167:245–48
     [Google Scholar]
  40. Enuka Y, Lauriola M, Feldman ME, Sas-Chen A, Ulitsky I, Yarden Y. 2016. Circular RNAs are long-lived and display only minimal early alterations in response to a growth factor. Nucleic Acids Res. 44:1370–83
     [Google Scholar]
  41. Errichelli L, Dini Modigliani S, Laneve P, Colantoni A, Legnini I et al. 2017. FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons. Nat. Commun. 8:14741
     [Google Scholar]
  42. Fan X, Zhang X, Wu X, Guo H, Hu Y et al. 2015. Single-cell RNA-seq transcriptome analysis of linear and circular RNAs in mouse preimplantation embryos. Genome Biol. 16:148
     [Google Scholar]
  43. Fei T, Chen Y, Xiao T, Li W, Cato L et al. 2017. Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. PNAS 114:E5207–15
     [Google Scholar]
  44. Fischer JW, Busa VF, Shao Y, Leung AKL. 2020. Structure-mediated RNA decay by UPF1 and G3BP1. Mol. Cell 78:70–84.e6
     [Google Scholar]
  45. Flores R, Grubb D, Elleuch A, Nohales MA, Delgado S, Gago S. 2011. Rolling-circle replication of viroids, viroid-like satellite RNAs and hepatitis delta virus: variations on a theme. RNA Biol 8:200–6
     [Google Scholar]
  46. Flores R, Navarro JA, de la Pena M, Navarro B, Ambros S, Vera A 1999. Viroids with hammerhead ribozymes: some unique structural and functional aspects with respect to other members of the group. Biol. Chem. 380:849–54
     [Google Scholar]
  47. Fong N, Kim H, Zhou Y, Ji X, Qiu J et al. 2014. Pre-mRNA splicing is facilitated by an optimal RNA polymerase II elongation rate. Genes Dev. 28:2663–76
     [Google Scholar]
  48. Ford E, Ares M Jr. 1994. Synthesis of circular RNA in bacteria and yeast using RNA cyclase ribozymes derived from a group I intron of phage T4. PNAS 91:3117–21
     [Google Scholar]
  49. Gao L, Chang S, Xia W, Wang X, Zhang C et al. 2020. Circular RNAs from BOULE play conserved roles in protection against stress-induced fertility decline. Sci. Adv. 6:46eabb7426
     [Google Scholar]
  50. Gao X, Ma X-K, Li X, Li G-W, Liu C-X et al. 2022. Knockout of circRNAs by base editing back-splice sites of circularized exons. Genome Biol. 23:16
     [Google Scholar]
  51. Gao X, Xia X, Li F, Zhang M, Zhou H et al. 2021. Circular RNA-encoded oncogenic E-cadherin variant promotes glioblastoma tumorigenicity through activation of EGFR-STAT3 signalling. Nat. Cell Biol. 23:278–91
     [Google Scholar]
  52. Gao Y, Wang J, Zheng Y, Zhang J, Chen S, Zhao F 2016. Comprehensive identification of internal structure and alternative splicing events in circular RNAs. Nat. Commun. 7:12060
     [Google Scholar]
  53. Gao Y, Zhao F. 2018. Computational strategies for exploring circular RNAs. Trends Genet. 34:389–400
     [Google Scholar]
  54. Gardner EJ, Nizami ZF, Talbot CC Jr., Gall JG. 2012. Stable intronic sequence RNA (sisRNA), a new class of noncoding RNA from the oocyte nucleus of Xenopus tropicalis. Genes Dev. 26:2550–59
     [Google Scholar]
  55. Glazar P, Papavasileiou P, Rajewsky N. 2014. circBase: a database for circular RNAs. RNA 20:1666–70
     [Google Scholar]
  56. Grabowski PJ, Zaug AJ, Cech TR. 1981. The intervening sequence of the ribosomal RNA precursor is converted to a circular RNA in isolated nuclei of tetrahymena. Cell 23:467–76
     [Google Scholar]
  57. Graveley BR. 2008. Molecular biology: power sequencing. Nature 453:1197–98
     [Google Scholar]
  58. Guarnerio J, Bezzi M, Jeong JC, Paffenholz SV, Berry K et al. 2016. Oncogenic role of fusion-circRNAs derived from cancer-associated chromosomal translocations. Cell 165:289–302
     [Google Scholar]
  59. Guarnerio J, Zhang Y, Cheloni G, Panella R, Katon JM et al. 2019. Intragenic antagonistic roles of protein and circRNA in tumorigenesis. Cell Res. 29:628–40
     [Google Scholar]
  60. Guo JU, Agarwal V, Guo H, Bartel DP. 2014. Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 15:409
     [Google Scholar]
  61. Hanniford D, Ulloa-Morales A, Karz A, Berzoti-Coelho MG, Moubarak RS et al. 2020. Epigenetic silencing of CDR1as drives IGF2BP3-mediated melanoma invasion and metastasis. Cancer Cell 37:55–70.e15
     [Google Scholar]
  62. Hansen TB. 2018. Improved circRNA identification by combining prediction algorithms. Front. Cell Dev. Biol. 6:20
     [Google Scholar]
  63. Hansen TB. 2021. Signal and noise in circRNA translation. Methods 196:68–73
     [Google Scholar]
  64. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B et al. 2013. Natural RNA circles function as efficient microRNA sponges. Nature 495:384–88
     [Google Scholar]
  65. Hansen TB, Veno MT, Damgaard CK, Kjems J. 2016. Comparison of circular RNA prediction tools. Nucleic Acids Res. 44:e58
     [Google Scholar]
  66. Hansen TB, Wiklund ED, Bramsen JB, Villadsen SB, Statham AL et al. 2011. miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. EMBO J. 30:4414–22
     [Google Scholar]
  67. Hein MY, Hubner NC, Poser I, Cox J, Nagaraj N et al. 2015. A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 163:712–23
     [Google Scholar]
  68. Hensgens LA, Arnberg AC, Roosendaal E, Van Der Horst G, Van Der Veen R et al. 1983. Variation, transcription and circular RNAs of the mitochondrial gene for subunit I of cytochrome c oxidase. J. Mol. Biol. 164:35–58
     [Google Scholar]
  69. Holdt LM, Stahringer A, Sass K, Pichler G, Kulak NA et al. 2016. Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans. Nat. Commun. 7:12429
     [Google Scholar]
  70. Hsu MT, Coca-Prados M. 1979. Electron microscopic evidence for the circular form of RNA in the cytoplasm of eukaryotic cells. Nature 280:339–40
     [Google Scholar]
  71. Huang C, Liang D, Tatomer DC, Wilusz JE. 2018. A length-dependent evolutionarily conserved pathway controls nuclear export of circular RNAs. Genes Dev. 32:639–44
     [Google Scholar]
  72. Huang J-T, Chen J-N, Gong L-P, Bi Y-H, Liang J et al. 2019. Identification of virus-encoded circular RNA. Virology 529:144–51
     [Google Scholar]
  73. Huang R, Zhang Y, Han B, Bai Y, Zhou R et al. 2017. Circular RNA HIPK2 regulates astrocyte activation via cooperation of autophagy and ER stress by targeting MIR124–2HG. Autophagy 13:1722–41
     [Google Scholar]
  74. Inoue T, Sullivan FX, Cech TR. 1986. New reactions of the ribosomal RNA precursor of Tetrahymena and the mechanism of self-splicing. J. Mol. Biol. 189:143–65
     [Google Scholar]
  75. Ivanov A, Memczak S, Wyler E, Torti F, Porath HT et al. 2015. Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. Cell Rep. 10:170–77
     [Google Scholar]
  76. Jarrous N. 2017. Roles of RNase P and its subunits. Trends Genet. 33:594–603
     [Google Scholar]
  77. Jeck WR, Sharpless NE. 2014. Detecting and characterizing circular RNAs. Nat. Biotechnol. 32:453–61
     [Google Scholar]
  78. Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE et al. 2013. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 19:141–57
     [Google Scholar]
  79. Kelly S, Greenman C, Cook PR, Papantonis A. 2015. Exon skipping is correlated with exon circularization. J. Mol. Biol. 427:2414–17
     [Google Scholar]
  80. Khan MA, Reckman YJ, Aufiero S, van den Hoogenhof MM, van der Made I et al. 2016. RBM20 regulates circular RNA production from the Titin gene. Circ. Res. 119:996–1003
     [Google Scholar]
  81. Kjems J, Garrett RA. 1988. Novel splicing mechanism for the ribosomal RNA intron in the archaebacterium Desulfurococcus mobilis. Cell 54:693–703
     [Google Scholar]
  82. Kleaveland B, Shi CY, Stefano J, Bartel DP 2018. A network of noncoding regulatory RNAs acts in the mammalian brain. Cell 174:350–62.e17
     [Google Scholar]
  83. Kos A, Dijkema R, Arnberg AC, van der Meide PH, Schellekens H. 1986. The hepatitis delta (δ) virus possesses a circular RNA. Nature 323:558–60
     [Google Scholar]
  84. Kramer MC, Liang D, Tatomer DC, Gold B, March ZM et al. 2015. Combinatorial control of Drosophila circular RNA expression by intronic repeats, hnRNPs, and SR proteins. Genes Dev. 29:2168–82
     [Google Scholar]
  85. Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. 2019. The biogenesis, biology and characterization of circular RNAs. Nat. Rev. Genet. 20:675–91
     [Google Scholar]
  86. Kristensen LS, Okholm TLH, Veno MT, Kjems J. 2018. Circular RNAs are abundantly expressed and upregulated during human epidermal stem cell differentiation. RNA Biol 15:280–91
     [Google Scholar]
  87. Lasda E, Parker R. 2014. Circular RNAs: diversity of form and function. RNA 20:1829–42
     [Google Scholar]
  88. Legnini I, Di Timoteo G, Rossi F, Morlando M, Briganti F et al. 2017. Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis. Mol. Cell 66:22–37.e9
     [Google Scholar]
  89. Li A, Chen Y-S, Ping X-L, Yang X, Xiao W et al. 2017. Cytoplasmic m6A reader YTHDF3 promotes mRNA translation. Cell Res. 27:444–47
     [Google Scholar]
  90. Li Q, Wang Y, Wu S, Zhou Z, Ding X et al. 2019. CircACC1 regulates assembly and activation of AMPK complex under metabolic stress. Cell Metab. 30:157–73.e7
     [Google Scholar]
  91. Li S, Li X, Xue W, Zhang L, Yang LZ et al. 2021. Screening for functional circular RNAs using the CRISPR-Cas13 system. Nat. Methods 18:51–59
     [Google Scholar]
  92. Li X, Liu C-X, Xue W, Zhang Y, Jiang S et al. 2017. Coordinated circRNA biogenesis and function with NF90/NF110 in viral infection. Mol. Cell 67:214–27.e7
     [Google Scholar]
  93. Li X, Liu S, Zhang L, Issaian A, Hill RC et al. 2019. A unified mechanism for intron and exon definition and back-splicing. Nature 573:375–80
     [Google Scholar]
  94. Li X, Yang L, Chen L-L. 2018. The biogenesis, functions, and challenges of circular RNAs. Mol. Cell 71:428–42
     [Google Scholar]
  95. Li X, Zhang J-L, Lei Y-N, Liu X-Q, Xue W et al. 2021. Linking circular intronic RNA degradation and function in transcription by RNase H1. Sci. China Life Sci. 64:1795–809
     [Google Scholar]
  96. Li Y, Zheng Q, Bao C, Li S, Guo W et al. 2015. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 25:981–84
     [Google Scholar]
  97. Li Z, Huang C, Bao C, Chen L, Lin M et al. 2015. Exon-intron circular RNAs regulate transcription in the nucleus. Nat. Struct. Mol. Biol. 22:256–64
     [Google Scholar]
  98. Li-Pook-Than J, Bonen L. 2006. Multiple physical forms of excised group II intron RNAs in wheat mitochondria. Nucleic Acids Res. 34:2782–90
     [Google Scholar]
  99. Liang D, Tatomer DC, Luo Z, Wu H, Yang L et al. 2017. The output of protein-coding genes shifts to circular RNAs when the pre-mRNA processing machinery is limiting. Mol. Cell 68:940–54.e3
     [Google Scholar]
  100. Liang D, Tatomer DC, Wilusz JE. 2021. Use of circular RNAs as markers of readthrough transcription to identify factors regulating cleavage/polyadenylation events. Methods 196:121–28
     [Google Scholar]
  101. Liang D, Wilusz JE. 2014. Short intronic repeat sequences facilitate circular RNA production. Genes Dev. 28:2233–47
     [Google Scholar]
  102. Litke JL, Jaffrey SR. 2019. Highly efficient expression of circular RNA aptamers in cells using autocatalytic transcripts. Nat. Biotechnol. 37:667–75
     [Google Scholar]
  103. Liu B, Ye B, Zhu X, Yang L, Li H et al. 2020. An inducible circular RNA circKcnt2 inhibits ILC3 activation to facilitate colitis resolution. Nat. Commun. 11:4076
     [Google Scholar]
  104. Liu C-X, Guo S-K, Nan F, Xu Y-F, Yang L, Chen L-L 2022. RNA circles with minimized immunogenicity as potent PKR inhibitors. Mol. Cell 82:420–34.e6
     [Google Scholar]
  105. Liu C-X, Li X, Nan F, Jiang S, Gao X et al. 2019. Structure and degradation of circular RNAs regulate PKR activation in innate immunity. Cell 177:865–80.e21
     [Google Scholar]
  106. Liu Z, Tao C, Li S, Du M, Bai Y et al. 2021. circFL-seq reveals full-length circular RNAs with rolling circular reverse transcription and nanopore sequencing. eLife 10:e69457
     [Google Scholar]
  107. López-Jiménez E, Rojas AM, Andrés-León E. 2018. RNA sequencing and prediction tools for circular RNAs analysis. Adv. Exp. Med. Biol. 1087:17–33
     [Google Scholar]
  108. Lu T, Cui L, Zhou Y, Zhu C, Fan D et al. 2015. Transcriptome-wide investigation of circular RNAs in rice. RNA 21:2076–87
     [Google Scholar]
  109. Ma X-K, Wang M-R, Liu C-X, Dong R, Carmichael GG et al. 2019. CIRCexplorer3: a CLEAR pipeline for direct comparison of circular and linear RNA expression. Genom. Proteom. Bioinform. 17:511–21
     [Google Scholar]
  110. Ma X-K, Xue W, Chen L-L, Yang L 2021. CIRCexplorer pipelines for circRNA annotation and quantification from non-polyadenylated RNA-seq datasets. Methods 196:3–10
     [Google Scholar]
  111. Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J et al. 2013. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495:333–38
     [Google Scholar]
  112. Memczak S, Papavasileiou P, Peters O, Rajewsky N. 2015. Identification and characterization of circular RNAs as a new class of putative biomarkers in human blood. PLOS ONE 10:e0141214
     [Google Scholar]
  113. Moldovan LI, Hansen TB, Veno MT, Okholm TLH, Andersen TL et al. 2019. High-throughput RNA sequencing from paired lesional- and non-lesional skin reveals major alterations in the psoriasis circRNAome. BMC Med. Genom. 12:174
     [Google Scholar]
  114. Moldovan LI, Tsoi LC, Ranjitha U, Hager H, Weidinger S et al. 2021. Characterization of circular RNA transcriptomes in psoriasis and atopic dermatitis reveals disease-specific expression profiles. Exp. Dermatol. 30:1187–96
     [Google Scholar]
  115. Molina-Sánchez MD, Martinez-Abarca F, Toro N. 2006. Excision of the Sinorhizobium meliloti group II intron RmInt1 as circles in vivo. J. Biol. Chem. 281:28737–44
     [Google Scholar]
  116. Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B. 2008. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat. Methods 5:621–28
     [Google Scholar]
  117. Nielsen H, Fiskaa T, Birgisdottir AB, Haugen P, Einvik C, Johansen S. 2003. The ability to form full-length intron RNA circles is a general property of nuclear group I introns. RNA 9:1464–75
     [Google Scholar]
  118. Nigro JM, Cho KR, Fearon ER, Kern SE, Ruppert JM et al. 1991. Scrambled exons.. Cell 64:607–13
     [Google Scholar]
  119. Ottesen EW, Luo D, Seo J, Singh NN, Singh RN. 2019. Human Survival Motor Neuron genes generate a vast repertoire of circular RNAs. Nucleic Acids Res. 47:2884–905
     [Google Scholar]
  120. Pamudurti NR, Bartok O, Jens M, Ashwal-Fluss R, Stottmeister C et al. 2017. Translation of circRNAs. Mol. Cell 66:9–21.e7
     [Google Scholar]
  121. Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ. 2008. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat. Genet. 40:1413–15
     [Google Scholar]
  122. Panda AC, De S, Grammatikakis I, Munk R, Yang X et al. 2017. High-purity circular RNA isolation method (RPAD) reveals vast collection of intronic circRNAs. Nucleic Acids Res. 45:e116
     [Google Scholar]
  123. Park OH, Ha H, Lee Y, Boo SH, Kwon DH et al. 2019. Endoribonucleolytic cleavage of m6A-containing RNAs by RNase P/MRP complex. Mol. Cell 74:494–507.e8
     [Google Scholar]
  124. Pasman Z, Been MD, Garcia-Blanco MA. 1996. Exon circularization in mammalian nuclear extracts. RNA 2:603–10
     [Google Scholar]
  125. Piwecka M, Glažar P, Hernandez-Miranda LR, Memczak S, Wolf SA et al. 2017. Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science 357:eaam8526
     [Google Scholar]
  126. Rabani M, Levin JZ, Fan L, Adiconis X, Raychowdhury R et al. 2011. Metabolic labeling of RNA uncovers principles of RNA production and degradation dynamics in mammalian cells. Nat. Biotechnol. 29:436–42
     [Google Scholar]
  127. Rahimi K, Faerch Nielsen A, Veno MT, Kjems J 2021a. Nanopore long-read sequencing of circRNAs. Methods 196:23–29
     [Google Scholar]
  128. Rahimi K, Veno MT, Dupont DM, Kjems J 2021b. Nanopore sequencing of brain-derived full-length circRNAs reveals circRNA-specific exon usage, intron retention and microexons. Nat. Commun. 12: 4825.
     [Google Scholar]
  129. Roundtree IA, Luo G-Z, Zhang Z, Wang X, Zhou T et al. 2017. YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs. eLife 6:e31311
     [Google Scholar]
  130. Rybak-Wolf A, Stottmeister C, Glazar P, Jens M, Pino N et al. 2015. Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol. Cell 58:870–85
     [Google Scholar]
  131. Salgia SR, Singh SK, Gurha P, Gupta R. 2003. Two reactions of Haloferax volcanii RNA splicing enzymes: joining of exons and circularization of introns. RNA 9:319–30
     [Google Scholar]
  132. Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. 2011. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language?. Cell 146:353–58
     [Google Scholar]
  133. Salzman J, Chen RE, Olsen MN, Wang PL, Brown PO. 2013. Cell-type specific features of circular RNA expression. PLOS Genet. 9:e1003777
     [Google Scholar]
  134. Salzman J, Gawad C, Wang PL, Lacayo N, Brown PO. 2012. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLOS ONE 7:e30733
     [Google Scholar]
  135. Sanger HL, Klotz G, Riesner D, Gross HJ, Kleinschmidt AK. 1976. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. PNAS 73:3852–56
     [Google Scholar]
  136. Shi H, Wei J, He C. 2019. Where, when, and how: context-dependent functions of RNA methylation writers, readers, and erasers. Mol. Cell 74:640–50
     [Google Scholar]
  137. Singh SK, Gurha P, Tran EJ, Maxwell ES, Gupta R. 2004. Sequential 2′-O-methylation of archaeal pre-tRNATrp nucleotides is guided by the intron-encoded but trans-acting box C/D ribonucleoprotein of pre-tRNA. J. Biol. Chem. 279:47661–71
     [Google Scholar]
  138. Slyper M, Porter CBM, Ashenberg O, Waldman J, Drokhlyansky E et al. 2020. A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors. Nat. Med. 26:792–802
     [Google Scholar]
  139. Soma A, Onodera A, Sugahara J, Kanai A, Yachie N et al. 2007. Permuted tRNA genes expressed via a circular RNA intermediate in Cyanidioschyzon merolae. Science 318:450–53
     [Google Scholar]
  140. Stagsted LVW, Nielsen KM, Daugaard I, Hansen TB. 2019. Noncoding AUG circRNAs constitute an abundant and conserved subclass of circles. Life Sci. Alliance 2:398
     [Google Scholar]
  141. Stagsted LVW, O'Leary ET, Ebbesen KK, Hansen TB 2021. The RNA-binding protein SFPQ preserves long-intron splicing and regulates circRNA biogenesis in mammals. eLife 10:e63088
     [Google Scholar]
  142. Stark R, Grzelak M, Hadfield J. 2019. RNA sequencing: the teenage years. Nat. Rev. Genet. 20:631–56
     [Google Scholar]
  143. Starke S, Jost I, Rossbach O, Schneider T, Schreiner S et al. 2015. Exon circularization requires canonical splice signals. Cell Rep. 10:103–11
     [Google Scholar]
  144. Starostina NG, Marshburn S, Johnson LS, Eddy SR, Terns RM, Terns MP. 2004. Circular box C/D RNAs in Pyrococcus furiosus. PNAS 101:14097–101
     [Google Scholar]
  145. Suzuki H, Zuo Y, Wang J, Zhang MQ, Malhotra A, Mayeda A. 2006. Characterization of RNase R-digested cellular RNA source that consists of lariat and circular RNAs from pre-mRNA splicing. Nucleic Acids Res. 34:e63
     [Google Scholar]
  146. Szabo L, Morey R, Palpant NJ, Wang PL, Afari N et al. 2015. Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development. Genome Biol. 16:126
     [Google Scholar]
  147. Szabo L, Salzman J. 2016. Detecting circular RNAs: bioinformatic and experimental challenges. Nat. Rev. Genet. 17:679–92
     [Google Scholar]
  148. Tabak HF, Van der Horst G, Kamps AM, Arnberg AC. 1987. Interlocked RNA circle formation by a self-splicing yeast mitochondrial group I intron. Cell 48:101–10
     [Google Scholar]
  149. Tagawa T, Gao S, Koparde VN, Gonzalez M, Spouge JL et al. 2018. Discovery of Kaposi's sarcoma herpesvirus-encoded circular RNAs and a human antiviral circular RNA. PNAS 115:12805–10
     [Google Scholar]
  150. Talhouarne GJ, Gall JG. 2014. Lariat intronic RNAs in the cytoplasm of Xenopus tropicalis oocytes. RNA 20:1476–87
     [Google Scholar]
  151. Tang C, Xie Y, Yu T, Liu N, Wang Z et al. 2020. m6A-dependent biogenesis of circular RNAs in male germ cells. Cell Res. 30:211–28
     [Google Scholar]
  152. Tang C, Yu T, Xie Y, Wang Z, McSwiggin H et al. 2018. Template switching causes artificial junction formation and false identification of circular RNAs. bioRxiv 259556. https://doi.org/10.1101/259556
    [Crossref]
  153. Tang TH, Rozhdestvensky TS, d'Orval BC, Bortolin ML, Huber H et al. 2002. RNomics in Archaea reveals a further link between splicing of archaeal introns and rRNA processing. Nucleic Acids Res. 30:921–30
     [Google Scholar]
  154. Tay ML, Pek JW. 2017. Maternally inherited stable intronic sequence RNA triggers a self-reinforcing feedback loop during development. Curr. Biol. 27:1062–67
     [Google Scholar]
  155. Toptan T, Abere B, Nalesnik MA, Swerdlow SH, Ranganathan S et al. 2018. Circular DNA tumor viruses make circular RNAs. PNAS 115:E8737–45
     [Google Scholar]
  156. Ungerleider N, Concha M, Lin Z, Roberts C, Wang X et al. 2018. The Epstein Barr virus circRNAome. PLOS Pathog. 14:e1007206
     [Google Scholar]
  157. van Heesch S, Witte F, Schneider-Lunitz V, Schulz JF, Adami E et al. 2019. The translational landscape of the human heart. Cell 178:242–60.e29
     [Google Scholar]
  158. Veno MT, Hansen TB, Veno ST, Clausen BH, Grebing M et al. 2015. Spatio-temporal regulation of circular RNA expression during porcine embryonic brain development. Genome Biol. 16:245
     [Google Scholar]
  159. Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L et al. 2019. The landscape of circular RNA in cancer. Cell 176:869–81.e13
     [Google Scholar]
  160. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L et al. 2008. Alternative isoform regulation in human tissue transcriptomes. Nature 456:470–76
     [Google Scholar]
  161. Wang M, Hou J, Muller-McNicoll M, Chen W, Schuman EM 2019. Long and repeat-rich intronic sequences favor circular RNA formation under conditions of reduced spliceosome activity. iScience 20:237–47
     [Google Scholar]
  162. Wang Y, Wang Z. 2015. Efficient backsplicing produces translatable circular mRNAs. RNA 21:172–79
     [Google Scholar]
  163. Weigelt CM, Sehgal R, Tain LS, Cheng J, Esser J et al. 2020. An insulin-sensitive circular RNA that regulates lifespan in Drosophila. Mol. Cell 79:268–79
     [Google Scholar]
  164. Wesselhoeft RA, Kowalski PS, Anderson DG. 2018. Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat. Commun. 9:2629
     [Google Scholar]
  165. Wesselhoeft RA, Kowalski PS, Parker-Hale FC, Huang Y, Bisaria N, Anderson DG. 2019. RNA circularization diminishes immunogenicity and can extend translation duration in vivo. Mol. Cell 74:508–20.e4
     [Google Scholar]
  166. Westholm JO, Miura P, Olson S, Shenker S, Joseph B et al. 2014. Genome-wide analysis of Drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation. Cell Rep. 9:1966–80
     [Google Scholar]
  167. Wilhelm BT, Marguerat S, Watt S, Schubert F, Wood V et al. 2008. Dynamic repertoire of a eukaryotic transcriptome surveyed at single-nucleotide resolution. Nature 453:1239–43
     [Google Scholar]
  168. Wilusz JE. 2018. A 360° view of circular RNAs: from biogenesis to functions. Wiley Interdiscip. Rev. RNA 9:e1478
     [Google Scholar]
  169. Wu K, Liao X, Gong Y, He J, Zhou J-K et al. 2019. Circular RNA F-circSR derived from SLC34A2-ROS1 fusion gene promotes cell migration in non-small cell lung cancer. Mol. Cancer 18:98
     [Google Scholar]
  170. Wu W, Ji P, Zhao F 2020. CircAtlas: an integrated resource of one million highly accurate circular RNAs from 1070 vertebrate transcriptomes. Genome Biol. 21:101
     [Google Scholar]
  171. Xia P, Wang S, Ye B, Du Y, Li C et al. 2018. A circular RNA protects dormant hematopoietic stem cells from DNA sensor cGAS-mediated exhaustion. Immunity 48:688–701.e7
     [Google Scholar]
  172. Xiao M-S, Ai Y, Wilusz JE 2020. Biogenesis and functions of circular RNAs come into focus. Trends Cell Biol. 30:226–40
     [Google Scholar]
  173. Xiao M-S, Wilusz JE. 2019. An improved method for circular RNA purification using RNase R that efficiently removes linear RNAs containing G-quadruplexes or structured 3′ ends. Nucleic Acids Res. 47:8755–69
     [Google Scholar]
  174. Xin R, Gao Y, Gao Y, Wang R, Kadash-Edmondson KE et al. 2021. isoCirc catalogs full-length circular RNA isoforms in human transcriptomes. Nat. Commun. 12:266
     [Google Scholar]
  175. Xu H, Guo S, Li W, Yu P 2015. The circular RNA Cdr1as, via miR-7 and its targets, regulates insulin transcription and secretion in islet cells. Sci. Rep. 5:12453
     [Google Scholar]
  176. Yang L, Duff MO, Graveley BR, Carmichael GG, Chen L-L. 2011. Genomewide characterization of non-polyadenylated RNAs. Genome Biol. 12:R16
     [Google Scholar]
  177. Yang Y, Fan X, Mao M, Song X, Wu P et al. 2017. Extensive translation of circular RNAs driven by N6-methyladenosine. Cell Res. 27:626–41
     [Google Scholar]
  178. You X, Vlatkovic I, Babic A, Will T, Epstein I et al. 2015. Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nat. Neurosci. 18:603–10
     [Google Scholar]
  179. Yu C-Y, Li T-C, Wu Y-Y, Yeh C-H, Chiang W et al. 2017. The circular RNA circBIRC6 participates in the molecular circuitry controlling human pluripotency. Nat. Commun. 8:1149
     [Google Scholar]
  180. Yu C-Y, Liu H-J, Hung L-Y, Kuo H-C, Chuang T-J. 2014. Is an observed non-co-linear RNA product spliced in trans, in cis or just in vitro?. Nucleic Acids Res. 42:9410–23
     [Google Scholar]
  181. Zaphiropoulos PG. 1996. Circular RNAs from transcripts of the rat cytochrome P450 2C24 gene: correlation with exon skipping. PNAS 93:6536–41
     [Google Scholar]
  182. Zeng X, Lin W, Guo M, Zou Q. 2017. A comprehensive overview and evaluation of circular RNA detection tools. PLOS Comput. Biol. 13:e1005420
     [Google Scholar]
  183. Zeng Y, Du WW, Wu Y, Yang Z, Awan FM. 2017. A circular RNA binds to and activates AKT phosphorylation and nuclear localization reducing apoptosis and enhancing cardiac repair. Theranostics 16:3842–55
     [Google Scholar]
  184. Zhang J, Hou L, Zuo Z, Ji P, Zhang X et al. 2021. Comprehensive profiling of circular RNAs with nanopore sequencing and CIRI-long. Nat. Biotechnol. 39:836–45
     [Google Scholar]
  185. Zhang J, Zhao F. 2021. Reconstruction of circular RNAs using Illumina and Nanopore RNA-seq datasets. Methods 196:17–22
     [Google Scholar]
  186. Zhang X-O, Dong R, Zhang Y, Zhang J-L, Luo Z et al. 2016. Diverse alternative back-splicing and alternative splicing landscape of circular RNAs. Genome Res. 26:1277–87
     [Google Scholar]
  187. Zhang X-O, Wang H-B, Zhang Y, Lu X, Chen L-L, Yang L 2014. Complementary sequence-mediated exon circularization. Cell 159:134–47
     [Google Scholar]
  188. Zhang Y, Nguyen TM, Zhang XO, Wang L, Phan T et al. 2021. Optimized RNA-targeting CRISPR/Cas13d technology outperforms shRNA in identifying functional circRNAs. Genome Biol. 22:41
     [Google Scholar]
  189. Zhang Y, Xue W, Li X, Zhang J, Chen S et al. 2016a. The biogenesis of nascent circular RNAs. Cell Rep. 15:611–24
     [Google Scholar]
  190. Zhang Y, Yang L, Chen L-L. 2016b. Characterization of circular RNAs. Methods Mol. Biol. 1402:215–27
     [Google Scholar]
  191. Zhang Y, Zhang X-O, Chen T, Xiang J-F, Yin Q-F et al. 2013. Circular intronic long noncoding RNAs. Mol. Cell 51:792–806
     [Google Scholar]
  192. Zhao J, Lee EE, Kim J, Yang R, Chamseddin B et al. 2019. Transforming activity of an oncoprotein-encoding circular RNA from human papillomavirus. Nat. Commun. 10:2300
     [Google Scholar]
  193. Zhao Q, Liu J, Deng H, Ma R, Liao J-Y et al. 2020. Targeting mitochondria-located circRNA SCAR alleviates NASH via reducing mROS output. Cell 183:76–93.e22
     [Google Scholar]
  194. Zheng Q, Bao C, Guo W, Li S, Chen J et al. 2016. Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat. Commun. 7:11215
     [Google Scholar]
  195. Zhou C, Molinie B, Daneshvar K, Pondick JV, Wang J et al. 2017. Genome-wide maps of m6A circRNAs identify widespread and cell-type-specific methylation patterns that are distinct from mRNAs. Cell Rep 20:2262–76
     [Google Scholar]
/content/journals/10.1146/annurev-cellbio-120420-125117
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Biogenesis and Regulatory Roles of Circular RNAs
Annual Review of Cell and Developmental Biology 38, 263 (2022); https://doi.org/10.1146/annurev-cellbio-120420-125117
/content/journals/10.1146/annurev-cellbio-120420-125117
/content/journals/10.1146/annurev-cellbio-120420-125117
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