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• W3100281716 abstract "Circular RNAs (circRNAs), a novel type of endogenous RNAs with covalently closed-loop structures, have become a new research hotspot in the RNA world. Their diversity, stability, evolutionary conservation, and cell type- or tissue-specific expression patterns endow circRNAs with various important biological functions. As a consequence, circRNAs are emerging as important regulators of physiological development and disease pathogenesis. Growing evidence has shown that circRNAs can regulate parental gene expression through diverse mechanisms, such as transcription and splicing regulation, microRNA (miRNA) sponges, mRNA traps, translational modulation, and post-translational modification. The study of circRNAs and how circRNAs regulate the expression of parental genes will facilitate a deeper understanding of their biological functions and provide new perspectives on their clinical application. Herein, we review the biogenesis of circRNAs, with a particular focus on the molecular mechanisms of circRNAs regulating their parental gene expression and the biological significance of such regulation. Circular RNAs (circRNAs), a novel type of endogenous RNAs with covalently closed-loop structures, have become a new research hotspot in the RNA world. Their diversity, stability, evolutionary conservation, and cell type- or tissue-specific expression patterns endow circRNAs with various important biological functions. As a consequence, circRNAs are emerging as important regulators of physiological development and disease pathogenesis. Growing evidence has shown that circRNAs can regulate parental gene expression through diverse mechanisms, such as transcription and splicing regulation, microRNA (miRNA) sponges, mRNA traps, translational modulation, and post-translational modification. The study of circRNAs and how circRNAs regulate the expression of parental genes will facilitate a deeper understanding of their biological functions and provide new perspectives on their clinical application. Herein, we review the biogenesis of circRNAs, with a particular focus on the molecular mechanisms of circRNAs regulating their parental gene expression and the biological significance of such regulation. Circular RNAs (circRNAs) are a novel group of endogenous transcripts generally characterized by their covalently closed-loop structures. The existence of circRNAs was first reported in 1976 when a group discovered circRNA molecules naturally existing in plant viroids.1Sanger H.L. Klotz G. Riesner D. Gross H.J. Kleinschmidt A.K. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures.Proc. Natl. Acad. Sci. USA. 1976; 73: 3852-3856Crossref PubMed Scopus (998) Google Scholar With advancements in RNA sequencing and bioinformatics analysis, large numbers of previously unannotated circRNAs have been identified in different organisms. Unlike linear RNAs, circRNAs lack free terminal structures since their 3′ and 5′ ends are joined together by covalent bonds.2Vicens Q. Westhof E. Biogenesis of circular RNAs.Cell. 2014; 159: 13-14Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar This unique structure enhances their stability and protects them from degradation by RNA exonuclease or RNase R.3Memczak S. Jens M. Elefsinioti A. Torti F. Krueger J. Rybak A. Maier L. Mackowiak S.D. Gregersen L.H. Munschauer M. et al.Circular RNAs are a large class of animal RNAs with regulatory potency.Nature. 2013; 495: 333-338Crossref PubMed Scopus (3821) Google Scholar,4Jeck W.R. Sorrentino J.A. Wang K. Slevin M.K. Burd C.E. Liu J. Marzluff W.F. Sharpless N.E. Circular RNAs are abundant, conserved, and associated with ALU repeats.RNA. 2013; 19: 141-157Crossref PubMed Scopus (2100) Google Scholar While most circRNAs are low in abundance, some are ubiquitously expressed and are present at higher copy numbers as compared to their linear transcripts.4Jeck W.R. Sorrentino J.A. Wang K. Slevin M.K. Burd C.E. Liu J. Marzluff W.F. Sharpless N.E. Circular RNAs are abundant, conserved, and associated with ALU repeats.RNA. 2013; 19: 141-157Crossref PubMed Scopus (2100) Google Scholar Moreover, most circRNAs are conserved across species and often exhibit cell type- or tissue-specific expression, suggesting potential regulatory roles.4Jeck W.R. Sorrentino J.A. Wang K. Slevin M.K. Burd C.E. Liu J. Marzluff W.F. Sharpless N.E. Circular RNAs are abundant, conserved, and associated with ALU repeats.RNA. 2013; 19: 141-157Crossref PubMed Scopus (2100) Google Scholar, 5Salzman J. Chen R.E. Olsen M.N. Wang P.L. Brown P.O. Cell-type specific features of circular RNA expression.PLoS Genet. 2013; 9: e1003777Crossref PubMed Scopus (1052) Google Scholar, 6Guo J.U. Agarwal V. Guo H. Bartel D.P. Expanded identification and characterization of mammalian circular RNAs.Genome Biol. 2014; 15: 409Crossref PubMed Scopus (877) Google Scholar Based on the source of the genome and biogenesis patterns, circRNAs are mainly divided into three groups: exonic circRNAs (EcircRNAs), exonic-intronic circRNAs (EIciRNAs), and circular intronic RNAs (ciRNAs).7Zhang X.-O. Wang H.-B. Zhang Y. Lu X. Chen L.-L. Yang L. Complementary sequence-mediated exon circularization.Cell. 2014; 159: 134-147Abstract Full Text Full Text PDF PubMed Scopus (928) Google Scholar, 8Li Z. Huang C. Bao C. Chen L. Lin M. Wang X. Zhong G. Yu B. Hu W. Dai L. et al.Exon-intron circular RNAs regulate transcription in the nucleus.Nat. Struct. Mol. Biol. 2015; 22: 256-264Crossref PubMed Scopus (1334) Google Scholar, 9Zhang Y. Zhang X.-O. Chen T. Xiang J.-F. Yin Q.-F. Xing Y.-H. Zhu S. Yang L. Chen L.-L. Circular intronic long noncoding RNAs.Mol. Cell. 2013; 51: 792-806Abstract Full Text Full Text PDF PubMed Scopus (1154) Google Scholar circRNAs have been reported to directly bind proteins, sponge microRNAs (miRNAs), and translate into proteins.10Holdt L.M. Stahringer A. Sass K. Pichler G. Kulak N.A. Wilfert W. Kohlmaier A. Herbst A. Northoff B.H. Nicolaou A. et al.Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans.Nat. Commun. 2016; 7: 12429Crossref PubMed Scopus (508) Google Scholar, 11Du W.W. Yang W. Chen Y. Wu Z.-K. Foster F.S. Yang Z. Li X. Yang B.B. Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses.Eur. Heart J. 2017; 38: 1402-1412Crossref PubMed Google Scholar, 12Hansen T.B. Jensen T.I. Clausen B.H. Bramsen J.B. Finsen B. Damgaard C.K. Kjems J. Natural RNA circles function as efficient microRNA sponges.Nature. 2013; 495: 384-388Crossref PubMed Scopus (3752) Google Scholar, 13Hansen T.B. Wiklund E.D. Bramsen J.B. Villadsen S.B. Statham A.L. Clark S.J. Kjems J. miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA.EMBO J. 2011; 30: 4414-4422Crossref PubMed Scopus (579) Google Scholar, 14Yang Y. Fan X. Mao M. Song X. Wu P. Zhang Y. Jin Y. Yang Y. Chen L.L. Wang Y. et al.Extensive translation of circular RNAs driven by N6-methyladenosine.Cell Res. 2017; 27: 626-641Crossref PubMed Scopus (671) Google Scholar However, emerging studies demonstrate that circRNAs can modulate the expression of their parental genes at multiple levels and are involved in the regulation of various physiological or pathological processes, including embryogenesis, atherosclerosis, and tumorigenesis.15Tay M.L. Pek J.W. Maternally inherited stable intronic sequence RNA triggers a self-reinforcing feedback loop during development.Curr. Biol. 2017; 27: 1062-1067Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 16Kong P. Yu Y. Wang L. Dou Y.Q. Zhang X.H. Cui Y. Wang H.Y. Yong Y.T. Liu Y.B. Hu H.J. et al.circ-Sirt1 controls NF-κB activation via sequence-specific interaction and enhancement of SIRT1 expression by binding to miR-132/212 in vascular smooth muscle cells.Nucleic Acids Res. 2019; 47: 3580-3593Crossref PubMed Scopus (35) Google Scholar, 17Zhou J. Zhang S. Chen Z. He Z. Xu Y. Li Z. circRNA-ENO1 promoted glycolysis and tumor progression in lung adenocarcinoma through upregulating its host gene ENO1.Cell Death Dis. 2019; 10: 885Crossref PubMed Scopus (53) Google Scholar, 18Du W.W. Yang W. Li X. Awan F.M. Yang Z. Fang L. Lyu J. Li F. Peng C. Krylov S.N. et al.A circular RNA circ-DNMT1 enhances breast cancer progression by activating autophagy.Oncogene. 2018; 37: 5829-5842Crossref PubMed Scopus (95) Google Scholar In this review, we briefly introduce the biogenesis of circRNAs, summarize their functional roles in regulating parental gene expression, and discuss the biological significance of their regulatory functions. Precursor (pre-)mRNAs are synthesized by RNA polymerase II (RNA Pol II) and canonically spliced into linear mRNAs. However, circRNAs are derived from back-splicing of pre-mRNAs, a novel mode of RNA splicing involving joining of the 3′ splice site to the 5′ splice site.3Memczak S. Jens M. Elefsinioti A. Torti F. Krueger J. Rybak A. Maier L. Mackowiak S.D. Gregersen L.H. Munschauer M. et al.Circular RNAs are a large class of animal RNAs with regulatory potency.Nature. 2013; 495: 333-338Crossref PubMed Scopus (3821) Google Scholar,19Starke S. Jost I. Rossbach O. Schneider T. Schreiner S. Hung L.H. Bindereif A. Exon circularization requires canonical splice signals.Cell Rep. 2015; 10: 103-111Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar Several mechanisms have been recently proposed for the formation of circRNAs (Figure 1).4Jeck W.R. Sorrentino J.A. Wang K. Slevin M.K. Burd C.E. Liu J. Marzluff W.F. Sharpless N.E. Circular RNAs are abundant, conserved, and associated with ALU repeats.RNA. 2013; 19: 141-157Crossref PubMed Scopus (2100) Google Scholar,9Zhang Y. Zhang X.-O. Chen T. Xiang J.-F. Yin Q.-F. Xing Y.-H. Zhu S. Yang L. Chen L.-L. Circular intronic long noncoding RNAs.Mol. Cell. 2013; 51: 792-806Abstract Full Text Full Text PDF PubMed Scopus (1154) Google Scholar,20Eger N. Schoppe L. Schuster S. Laufs U. Boeckel J.N. Circular RNA splicing.Adv. Exp. Med. Biol. 2018; 1087: 41-52Crossref PubMed Scopus (52) Google Scholar, 21Conn S.J. Pillman K.A. Toubia J. Conn V.M. Salmanidis M. Phillips C.A. et al.The RNA Binding Protein Quaking Regulates Formation of circRNAs.Cell. 2015; 160: 1125-1134Abstract Full Text Full Text PDF PubMed Scopus (965) Google Scholar, 22Errichelli L. Dini Modigliani S. Laneve P. Colantoni A. Legnini I. Capauto D. et al.FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons.Nat. Commun. 2017; 8: 14741Crossref PubMed Scopus (184) Google Scholar, 23Lu Z. Filonov G.S. Noto J.J. Schmidt C.A. Hatkevich T.L. Wen Y. Jaffrey S.R. Matera A.G. Metazoan tRNA introns generate stable circular RNAs in vivo.RNA. 2015; 21: 1554-1565Crossref PubMed Scopus (90) Google Scholar In 2013, Jeck et al.4Jeck W.R. Sorrentino J.A. Wang K. Slevin M.K. Burd C.E. Liu J. Marzluff W.F. Sharpless N.E. Circular RNAs are abundant, conserved, and associated with ALU repeats.RNA. 2013; 19: 141-157Crossref PubMed Scopus (2100) Google Scholar first put forward two models of circRNA circularization that were widely accepted, that is, lariat-driven circularization and intron pairing-driven circularization. The former requires covalent joining of 5′ donor splice sites and 3′ acceptor splice sites to form a lariat structure that contains at least one exon.4Jeck W.R. Sorrentino J.A. Wang K. Slevin M.K. Burd C.E. Liu J. Marzluff W.F. Sharpless N.E. Circular RNAs are abundant, conserved, and associated with ALU repeats.RNA. 2013; 19: 141-157Crossref PubMed Scopus (2100) Google Scholar,20Eger N. Schoppe L. Schuster S. Laufs U. Boeckel J.N. Circular RNA splicing.Adv. Exp. Med. Biol. 2018; 1087: 41-52Crossref PubMed Scopus (52) Google Scholar In some cases, an intronic lariat, which is formed when an intron is removed during pre-mRNA splicing, can produce ciRNA.9Zhang Y. Zhang X.-O. Chen T. Xiang J.-F. Yin Q.-F. Xing Y.-H. Zhu S. Yang L. Chen L.-L. Circular intronic long noncoding RNAs.Mol. Cell. 2013; 51: 792-806Abstract Full Text Full Text PDF PubMed Scopus (1154) Google Scholar Intron pairing-driven circularization is mostly related to complementary inverted sequences within the flanking introns of the back-spliced exons. In this model, the pairing between two introns can bracket the back-spliced exons and induce their circularization.4Jeck W.R. Sorrentino J.A. Wang K. Slevin M.K. Burd C.E. Liu J. Marzluff W.F. Sharpless N.E. Circular RNAs are abundant, conserved, and associated with ALU repeats.RNA. 2013; 19: 141-157Crossref PubMed Scopus (2100) Google Scholar,7Zhang X.-O. Wang H.-B. Zhang Y. Lu X. Chen L.-L. Yang L. Complementary sequence-mediated exon circularization.Cell. 2014; 159: 134-147Abstract Full Text Full Text PDF PubMed Scopus (928) Google Scholar In addition to the complementary sequences, some RNA-binding proteins (RBPs), such as QKI and FUS, can directly bind to specific RNA motifs in the introns on both sides of the circularized exons.4Jeck W.R. Sorrentino J.A. Wang K. Slevin M.K. Burd C.E. Liu J. Marzluff W.F. Sharpless N.E. Circular RNAs are abundant, conserved, and associated with ALU repeats.RNA. 2013; 19: 141-157Crossref PubMed Scopus (2100) Google Scholar,21Conn S.J. Pillman K.A. Toubia J. Conn V.M. Salmanidis M. Phillips C.A. et al.The RNA Binding Protein Quaking Regulates Formation of circRNAs.Cell. 2015; 160: 1125-1134Abstract Full Text Full Text PDF PubMed Scopus (965) Google Scholar,22Errichelli L. Dini Modigliani S. Laneve P. Colantoni A. Legnini I. Capauto D. et al.FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons.Nat. Commun. 2017; 8: 14741Crossref PubMed Scopus (184) Google Scholar Through the dimerization of these RBPs, the splice sites are brought into close proximity, and the spliceosome engages in a back-splicing reaction. A special class of circRNAs called tRNA intronic circRNAs (tricRNAs) were found to be generated during pre-tRNA splicing. In this case, the tRNA splicing endonuclease complex cleaves an intron at the bulge-helix-bulge motif of the pre-tRNA, and the released ends are ligated to form a tRNA and a tricRNA.23Lu Z. Filonov G.S. Noto J.J. Schmidt C.A. Hatkevich T.L. Wen Y. Jaffrey S.R. Matera A.G. Metazoan tRNA introns generate stable circular RNAs in vivo.RNA. 2015; 21: 1554-1565Crossref PubMed Scopus (90) Google Scholar As circRNAs can interface with DNA or RNA at the sequence level and fold into a unique tertiary structure capable of specific interactions with proteins, they are particularly well suited to regulate gene expression at multiple levels. Indeed, recent studies have uncovered many specific examples illustrating the involvement of circRNAs in their parental gene expression at different regulatory levels (Figure 2), which are summarized in Table 1.Table 1circRNAs involved in parental gene expressionMechanistic classificationcircRNAParental geneMechanismReferencesTranscriptional regulationcircEIF3J circPAIP2EIF3J PAIP2interact with RNA Pol II and U1 snRNA8Li Z. Huang C. Bao C. Chen L. Lin M. Wang X. Zhong G. Yu B. Hu W. Dai L. et al.Exon-intron circular RNAs regulate transcription in the nucleus.Nat. Struct. Mol. Biol. 2015; 22: 256-264Crossref PubMed Scopus (1334) Google Scholarci-ankrd52ANKRD52interacts with elongation RNA Pol II9Zhang Y. Zhang X.-O. Chen T. Xiang J.-F. Yin Q.-F. Xing Y.-H. Zhu S. Yang L. Chen L.-L. Circular intronic long noncoding RNAs.Mol. Cell. 2013; 51: 792-806Abstract Full Text Full Text PDF PubMed Scopus (1154) Google ScholarsisR-4dpnactivates an intronic enhancer15Tay M.L. Pek J.W. Maternally inherited stable intronic sequence RNA triggers a self-reinforcing feedback loop during development.Curr. Biol. 2017; 27: 1062-1067Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholarcirc-HuRHuRinteracts with transcriptional factor CNBP24Yang F. Hu A. Li D. Wang J. Guo Y. Liu Y. Li H. Chen Y. Wang X. Huang K. et al.circ-HuR suppresses HuR expression and gastric cancer progression by inhibiting CNBP transactivation.Mol. Cancer. 2019; 18: 158Crossref PubMed Scopus (53) Google ScholarFECR1FLI1induces DNA demethylation in the promoter25Chen N. Zhao G. Yan X. Lv Z. Yin H. Zhang S. Song W. Li X. Li L. Du Z. et al.A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1.Genome Biol. 2018; 19: 218Crossref PubMed Scopus (109) Google ScholarcircITGA7ITGA7suppresses the transcriptional factor RREB126Li X. Wang J. Zhang C. Lin C. Zhang J. Zhang W. Zhang W. Lu Y. Zheng L. Li X. Circular RNA circITGA7 inhibits colorectal cancer growth and metastasis by modulating the Ras pathway and upregulating transcription of its host gene ITGA7.J. Pathol. 2018; 246: 166-179Crossref PubMed Scopus (111) Google Scholarcirc-DAB1DAB1upregulates the transcriptional factor RBPJ27Chia W. Liu J. Huang Y.-G. Zhang C. A circular RNA derived from DAB1 promotes cell proliferation and osteogenic differentiation of BMSCs via RBPJ/DAB1 axis.Cell Death Dis. 2020; 11: 372Crossref PubMed Scopus (6) Google Scholarcirc-STAT3STAT3upregulates the transcriptional factor Gli228Liu Y. Song J. Liu Y. Zhou Z. Wang X. Transcription activation of circ-STAT3 induced by Gli2 promotes the progression of hepatoblastoma via acting as a sponge for miR-29a/b/c-3p to upregulate STAT3/Gli2.J. Exp. Clin. Cancer Res. 2020; 39: 101Crossref PubMed Scopus (5) Google ScholarSplicing regulationcircMblMBLcompetes with linear mRNA splicing29Ashwal-Fluss R. Meyer M. Pamudurti N.R. Ivanov A. Bartok O. Hanan M. Evantal N. Memczak S. Rajewsky N. Kadener S. circRNA biogenesis competes with pre-mRNA splicing.Mol. Cell. 2014; 56: 55-66Abstract Full Text Full Text PDF PubMed Scopus (1422) Google ScholarcircSEP3SEP3favors alternative splicing of SEP3 mRNA30Conn V.M. Hugouvieux V. Nayak A. Conos S.A. Capovilla G. Cildir G. Jourdain A. Tergaonkar V. Schmid M. Zubieta C. Conn S.J. A circRNA from SEPALLATA3 regulates splicing of its cognate mRNA through R-loop formation.Nat. Plants. 2017; 3: 17053Crossref PubMed Scopus (190) Google ScholarceRNAcirc-Sirt1SIRT1sponges miR-132/21216Kong P. Yu Y. Wang L. Dou Y.Q. Zhang X.H. Cui Y. Wang H.Y. Yong Y.T. Liu Y.B. Hu H.J. et al.circ-Sirt1 controls NF-κB activation via sequence-specific interaction and enhancement of SIRT1 expression by binding to miR-132/212 in vascular smooth muscle cells.Nucleic Acids Res. 2019; 47: 3580-3593Crossref PubMed Scopus (35) Google Scholarcirc-ENO1ENO1sponges miR-22-3p17Zhou J. Zhang S. Chen Z. He Z. Xu Y. Li Z. circRNA-ENO1 promoted glycolysis and tumor progression in lung adenocarcinoma through upregulating its host gene ENO1.Cell Death Dis. 2019; 10: 885Crossref PubMed Scopus (53) Google ScholarcTFRCTFRCsponges miR-10731Su H. Tao T. Yang Z. Kang X. Zhang X. Kang D. Wu S. Li C. Circular RNA cTFRC acts as the sponge of microRNA-107 to promote bladder carcinoma progression.Mol. Cancer. 2019; 18: 27Crossref PubMed Scopus (95) Google ScholarcircFBLIM1FBLIM1sponges miR-34632Bai N. Peng E. Qiu X. Lyu N. Zhang Z. Tao Y. Li X. Wang Z. circFBLIM1 act as a ceRNA to promote hepatocellular cancer progression by sponging miR-346.J. Exp. Clin. Cancer Res. 2018; 37: 172Crossref PubMed Scopus (79) Google ScholarcircGFRA1GFRA1sponges miR-34a33He R. Liu P. Xie X. Zhou Y. Liao Q. Xiong W. Li X. Li G. Zeng Z. Tang H. circGFRA1 and GFRA1 act as ceRNAs in triple negative breast cancer by regulating miR-34a.J. Exp. Clin. Cancer Res. 2017; 36: 145Crossref PubMed Scopus (186) Google ScholarcircAmotl1Amotl1sponges miR-485-5p34Ou R. Lv J. Zhang Q. Lin F. Zhu L. Huang F. Li X. Li T. Zhao L. Ren Y. Xu Y. circAMOTL1 motivates AMOTL1 expression to facilitate cervical cancer growth.Mol. Ther. Nucleic Acids. 2020; 19: 50-60Abstract Full Text Full Text PDF PubMed Google Scholarcirc-VANGL1VANGL1sponges miR-605-3p35Zeng Z. Zhou W. Duan L. Zhang J. Lu X. Jin L. Yu Y. Circular RNA circ-VANGL1 as a competing endogenous RNA contributes to bladder cancer progression by regulating miR-605-3p/VANGL1 pathway.J. Cell. Physiol. 2019; 234: 3887-3896Crossref PubMed Scopus (42) Google Scholarcir-ITCHITCHsponges miR-7 and miR-20a36Huang G. Zhu H. Shi Y. Wu W. Cai H. Chen X. cir-ITCH plays an inhibitory role in colorectal cancer by regulating the Wnt/β-catenin pathway.PLoS ONE. 2015; 10: e0131225PubMed Google ScholarcircSMO742SMOsponges miR-338-3p37Xiong Z. Zhou C. Wang L. Zhu R. Zhong L. Wan D. Wang Q. Circular RNA SMO sponges miR-338-3p to promote the growth of glioma by enhancing the expression of SMO.Aging (Albany NY). 2019; 11: 12345-12360Crossref PubMed Scopus (12) Google Scholarcirc-AKT1AKT1sponges miR-942-5p38Ou R. Mo L. Tang H. Leng S. Zhu H. Zhao L. Ren Y. Xu Y. circRNA-AKT1 sequesters miR-942-5p to upregulate AKT1 and promote cervical cancer progression.Mol. Ther. Nucleic Acids. 2020; 20: 308-322Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholarcirc-TFF1TFF1sponges miR-32639Pan G. Mao A. Liu J. Lu J. Ding J. Liu W. Circular RNA hsa_circ_0061825 (circ-TFF1) contributes to breast cancer progression through targeting miR-326/TFF1 signalling.Cell Prolif. 2020; 53: e12720Crossref PubMed Scopus (24) Google ScholarmRNA trapHIPK2/3 circRNAsHIPK2/3sequester ATG translation start site4Jeck W.R. Sorrentino J.A. Wang K. Slevin M.K. Burd C.E. Liu J. Marzluff W.F. Sharpless N.E. Circular RNAs are abundant, conserved, and associated with ALU repeats.RNA. 2013; 19: 141-157Crossref PubMed Scopus (2100) Google Scholarcircular FmnFmnsequesters 5′ UTR exons40Chao C.W. Chan D.C. Kuo A. Leder P. The mouse formin (Fmn) gene: abundant circular RNA transcripts and gene-targeted deletion analysis.Mol. Med. 1998; 4: 614-628Crossref PubMed Google Scholardystrophin exonic circRNAsdystrophinlead to inactive dystrophin transcripts41Gualandi F. Trabanelli C. Rimessi P. Calzolari E. Toffolatti L. Patarnello T. Kunz G. Muntoni F. Ferlini A. Multiple exon skipping and RNA circularisation contribute to the severe phenotypic expression of exon 5 dystrophin deletion.J. Med. Genet. 2003; 40: e100Crossref PubMed Scopus (37) Google ScholarTranslational regulationcirc-Dnmt1Dnmt1promotes nuclear translocation of AUF118Du W.W. Yang W. Li X. Awan F.M. Yang Z. Fang L. Lyu J. Li F. Peng C. Krylov S.N. et al.A circular RNA circ-DNMT1 enhances breast cancer progression by activating autophagy.Oncogene. 2018; 37: 5829-5842Crossref PubMed Scopus (95) Google ScholarcircYapYapcompetitively interacts with eIF4G and PABP42Wu N. Yuan Z. Du K.Y. Fang L. Lyu J. Zhang C. He A. Eshaghi E. Zeng K. Ma J. et al.Translation of yes-associated protein (YAP) was antagonized by its circular RNA via suppressing the assembly of the translation initiation machinery.Cell Death Differ. 2019; 26: 2758-2773Crossref PubMed Scopus (39) Google ScholarcircPABPN1PABPN1competitively interacts with HuR43Abdelmohsen K. Panda A.C. Munk R. Grammatikakis I. Dudekula D.B. De S. Kim J. Noh J.H. Kim K.M. Martindale J.L. Gorospe M. Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1.RNA Biol. 2017; 14: 361-369Crossref PubMed Scopus (330) Google Scholarcirc-MMP9MMP9competitively interacts with AUF144Xia B. Hong T. He X. Hu X. Gao Y. A circular RNA derived from MMP9 facilitates oral squamous cell carcinoma metastasis through regulation of MMP9 mRNA stability.Cell Transplant. 2019; 28: 1614-1623Crossref PubMed Scopus (19) Google ScholarPost-translational regulationcircFBXW7FBXW7encodes the FBXW7-185aa protein45Ye F. Gao G. Zou Y. Zheng S. Zhang L. Ou X. Xie X. Tang H. circFBXW7 inhibits malignant progression by sponging miR-197-3p and encoding a 185-aa protein in triple-negative breast cancer.Mol. Ther. Nucleic Acids. 2019; 18: 88-98Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholarcirc-SPHRHSPHRHencodes the SHPRH-146aa protein46Zhang M. Huang N. Yang X. Luo J. Yan S. Xiao F. Chen W. Gao X. Zhao K. Zhou H. et al.A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis.Oncogene. 2018; 37: 1805-1814Crossref PubMed Scopus (248) Google Scholarcircβ-cateninβ-cateninencodes the β-catenin-370aa protein47Liang W.C. Wong C.W. Liang P.P. Shi M. Cao Y. Rao S.T. Tsui S.K. Waye M.M. Zhang Q. Fu W.M. Zhang J.F. Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway.Genome Biol. 2019; 20: 84Crossref PubMed Scopus (135) Google Scholarcirc-AKT3AKT3encodes the AKT3-174aa protein48Xia X. Li X. Li F. Wu X. Zhang M. Zhou H. Huang N. Yang X. Xiao F. Liu D. et al.A novel tumor suppressor protein encoded by circular AKT3 RNA inhibits glioblastoma tumorigenicity by competing with active phosphoinositide-dependent kinase-1.Mol. Cancer. 2019; 18: 131Crossref PubMed Scopus (65) Google Scholar Open table in a new tab In eukaryotes, transcription of protein-coding genes is performed by RNA Pol II.49Das G. Hinkley C.S. Herr W. Basal promoter elements as a selective determinant of transcriptional activator function.Nature. 1995; 374: 657-660Crossref PubMed Scopus (99) Google Scholar, 50Roeder R.G. Rutter W.J. Multiple forms of DNA-dependent RNA polymerase in eukaryotic organisms.Nature. 1969; 224: 234-237Crossref PubMed Scopus (575) Google Scholar, 51Juven-Gershon T. Kadonaga J.T. Regulation of gene expression via the core promoter and the basal transcriptional machinery.Dev. Biol. 2010; 339: 225-229Crossref PubMed Scopus (303) Google Scholar Genes transcribed by RNA Pol II typically require transcriptional regulatory elements (core promoters, proximal promoters, distal enhancers, and silencers) and the molecular machinery (general transcription factors, activators, and coactivators) that interacts with the regulatory elements to mediate precisely controlled patterns of gene expression. A growing body of evidence supports the role of circRNAs in the regulation of their parental gene transcription mediated by the transcriptional complex.8Li Z. Huang C. Bao C. Chen L. Lin M. Wang X. Zhong G. Yu B. Hu W. Dai L. et al.Exon-intron circular RNAs regulate transcription in the nucleus.Nat. Struct. Mol. Biol. 2015; 22: 256-264Crossref PubMed Scopus (1334) Google Scholar,9Zhang Y. Zhang X.-O. Chen T. Xiang J.-F. Yin Q.-F. Xing Y.-H. Zhu S. Yang L. Chen L.-L. Circular intronic long noncoding RNAs.Mol. Cell. 2013; 51: 792-806Abstract Full Text Full Text PDF PubMed Scopus (1154) Google Scholar,25Chen N. Zhao G. Yan X. Lv Z. Yin H. Zhang S. Song W. Li X. Li L. Du Z. et al.A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1.Genome Biol. 2018; 19: 218Crossref PubMed Scopus (109) Google Scholar,26Li X. Wang J. Zhang C. Lin C. Zhang J. Zhang W. Zhang W. Lu Y. Zheng L. Li X. Circular RNA circITGA7 inhibits colorectal cancer growth and metastasis by modulating the Ras pathway and upregulating transcription of its host gene ITGA7.J. Pathol. 2018; 246: 166-179Crossref PubMed Scopus (111) Google Scholar Some nuclear circRNAs can interact with RNA Pol II or transcriptional factors. For example, ci-ankrd52 accumulates to its sites of transcription, interacts with an elongation RNA Pol II complex, and acts as a positive transcriptional regulator of its parental gene.9Zhang Y. Zhang X.-O. Chen T. Xiang J.-F. Yin Q.-F. Xing Y.-H. Zhu S. Yang L. Chen L.-L. Circular intronic long noncoding RNAs.Mol. Cell. 2013; 51: 792-806Abstract Full Text Full Text PDF PubMed Scopus (1154) Google Scholar EIciRNAs, such as circEIF3J and circPAIP2, have been found to hold factors such as U1 small nuclear ribonucleoprotein (snRNP) through RNA-RNA interaction between U1 small nuclear RNA (snRNA) and EIciRNA, and the EIciRNA-U1 snRNP complexes subsequently interact with the RNA Pol II transcription complex at the promoters of parental genes to enhance gene expression.8Li Z. Huang C. Bao C. Chen L. Lin M. Wang X. Zhong G. Yu B. Hu W. Dai L. et al.Exon-intron circular RNAs regulate transcription in the nucleus.Nat. Struct. Mol. Biol. 2015; 22: 256-264Crossref PubMed Scopus (1334) Google Scholar Another circRNA, circ-HuR, can inhibit the transcription of HuR by repressing the binding of CCHC-type zinc finger nucleic acid-binding protein (CNBP) to the HuR promoter and suppress the growth and aggressiveness of gastric cancer.24Yang F. Hu A. Li D. Wang J. Guo Y. Liu Y. Li H. Chen Y. Wang X. Huang K. et al.circ-HuR suppresses HuR expression and gastric cancer progression by inhibiting CNBP transactivation.Mol. Cancer. 2019; 18: 158Crossref PubMed Scopus (53) Google Scholar Certain nuclear circRNAs may activate parental gene transcription by inducing DNA hypomethylation in the promoter or by regulating intronic enhancer. For instance, a novel FLI1 exonic circRNA, FECR1, utilizes a positive feedback mechanism to activate FLI1 transcription by inducing DNA hypomethylation in the CpG islands of its promoter.25Chen N. Zhao G. Yan X. Lv Z. Yin H. Zhang S. Song W. Li X. Li L. Du Z. et al.A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1.Genome Biol. 2018; 19: 218Crossref PubMed Scopus (109) Google Scholar Thus, FLI1 can regulate metastasis in breast cancer by using epigenetic mechanisms mediated by its exonic circRNA.25Chen N. Zhao G. Yan X. Lv Z. Yin H. Zhang S. Song W. Li X. Li L. Du Z. et al.A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1.Genome Biol. 2018; 19: 218Crossref PubMed Scopus (109) Google Scholar In Drosophila, a maternally inherited circular stable intronic sequence RNA (sisR-4) promotes transcription of its parental gene by activating an intronic enhancer during embryogenesis.15Tay M.L. Pek J.W. Maternally inherited stable intronic sequence RNA triggers a self-reinforcing feedback loop during development.Curr. Biol. 2017; 27: 1062-1067Abstract Full Text Full Text PDF PubMed Scopus (24) Google Schol" @default.
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