Regulation of circRNA biogenesis
Open accessAbstract
Unlike linear RNAs terminated with 5' caps and 3' tails, circular RNAs are characterized by covalently closed loop structures with neither 5' to 3' polarity nor polyadenylated tail. This intrinsic characteristic has led to the general under-estimation of the existence of circular RNAs in previous polyadenylated transcriptome analyses. With the advent of specific biochemical and computational approaches, a large number of circular RNAs from back-spliced exons (circRNAs) have been identified in various cell lines and across different species. Recent studies have uncovered that back-splicing requires canonical spliceosomal machinery and can be facilitated by both complementary sequences and specific protein factors. In this review, we highlight our current understanding of the regulation of circRNA biogenesis, including both the competition between splicing and back-splicing and the previously under-appreciated alternative circularization.
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Endogenous circRNAs lack the free ends necessary for exonuclease-mediated degradation, rendering them resistant to several mechanisms of RNA turnover and granting them extended lifespans compared to linear mRNA counterparts.
“endogenous circRNAs lack the free ends necessary for exonuclease-mediated degradation, rendering them resistant to several mechanisms of RNA turnover and granting them extended lifespans as compared to their linear mRNA counterparts2, 9.”
From Engineering circular RNA for potent and stable translation in eukaryotic cells (2018) · cites this paper as [2]
The opening section describes circRNAs as covalently closed loops without the ends of linear RNAs, and “Regulate the Competition Between Canonical Splicing and Back-Splicing” states that they are more stable as closed circles (page numbers unavailable). The copy does not specify exonuclease-mediated degradation or establish resistance to several RNA-turnover mechanisms, so those mechanistic details are not supported. (LLM, conf=0.84)
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Cites
Circular RNAs are a large class of animal RNAs with regulatory potency
Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J., Rybak, A., Maier, L., Mackowiak, S. D., Gregersen, L. H., Munschauer, M., et al. (2013) · Nature · doi:10.1038/nature11928 · Cited by 7,990 · see citing works
Natural RNA circles function as efficient microRNA sponges
Hansen, T. B., Jensen, T. I., Clausen, B. H., Bramsen, J. B., Finsen, B., Damgaard, C. K., & Kjems, J. (2013) · Nature · doi:10.1038/nature11993 · Cited by 7,985 · see citing works
Circular RNAs are abundant, conserved, and associated with ALU repeats
Jeck, W. R., Sorrentino, J. A., Wang, K., Slevin, M. K., Burd, C. E., Liu, J., Marzluff, W. F., & Sharpless, N. E. (2013) · RNA · doi:10.1261/rna.035667.112 · Cited by 4,388 · see citing works
circRNA biogenesis competes with pre-mRNA splicing
Ashwal-Fluss, R., Meyer, M., Pamudurti, N. R., Ivanov, A., Bartok, O., Hanan, M., Evantal, N., Memczak, S., Rajewsky, N., & Kadener, S. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.08.019 · Cited by 3,083 · see citing works
Exon-intron circular RNAs regulate transcription in the nucleus
Li, Z., Huang, C., Bao, C., Chen, L., Lin, M., Wang, X., Zhong, G., Yu, B., Hu, W., Dai, L., et al. (2015) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2959 · Cited by 2,905 · see citing works
Self-citationDetecting and characterizing circular RNAs
Jeck, W. R., & Sharpless, N. E. (2014) · Nature Biotechnology · doi:10.1038/nbt.2890 · Cited by 2,685 · see citing works
Salzman, J., Gawad, C., Wang, P. L., Lacayo, N. J., & Brown, P. O. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030733 · Cited by 2,457 · see citing works
Sanger, H. L., Klotz, G., Riesner, D., Gross, H. J., & Kleinschmidt, A. K. (1976) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.73.11.3852 · Cited by 2,296 · see citing works
Circular intronic long noncoding RNAs
Zhang, Y., Zhang, X.-O., Chen, T., Xiang, J.-F., Yin, Q.-F., Xing, Y.-H., Zhu, S., Yang, L., & Chen, L.-L. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.08.017 · Cited by 2,221 · see citing works
Self-citationInsights into RNA Biology from an Atlas of Mammalian mRNA-Binding Proteins
Castello, A., Fischer, B., Eichelbaum, K., Horos, R., Beckmann, B. M., Strein, C., Davey, N. E., Humphreys, D. T., Preiss, T., Steinmetz, L. M., et al. (2012) · Cell · doi:10.1016/j.cell.2012.04.031 · Cited by 2,132 · see citing works
Complementary Sequence-Mediated Exon Circularization
Zhang, X.-O., Wang, H.-B., Zhang, Y., Lu, X., Chen, L.-L., & Yang, L. (2014) · Cell · doi:10.1016/j.cell.2014.09.001 · Cited by 1,999 · cited 19× · see citing works
“The biogenesis of circRNAs via backsplicing is different from the canonical splicing of linear RNAs.(12) Interestingly, it is also distinct from the formation of other types of circular RNAs, including but not limited to those generated by direct single strand RNA ligation,(26) derived from intermediates of processed…”
BackgroundInfluentialSelf-citationCell-Type Specific Features of Circular RNA Expression
Salzman, J., Chen, R. E., Olsen, M. N., Wang, P. L., & Brown, P. O. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003777 · Cited by 1,955 · see citing works
Expanded identification and characterization of mammalian circular RNAs
Guo, J. U., Agarwal, V., Guo, H., & Bartel, D. P. (2014) · Genome biology · doi:10.1186/s13059-014-0409-z · Cited by 1,578 · see citing works
Mis-splicing yields circular RNA molecules.
Cocquerelle, C., Mascrez, B., Hétuin, D., & Bailleul, B. (1993) · The FASEB Journal · doi:10.1096/fasebj.7.1.7678559 · Cited by 1,197 · see citing works
Circular RNAs: diversity of form and function
Lasda, E. L., & Parker, R. (2014) · RNA · doi:10.1261/rna.047126.114 · Cited by 1,193 · see citing works
Circular transcripts of the testis-determining gene Sry in adult mouse testis
Capel, B., Swain, A., Nicolis, S. K., Hacker, A., Walter, M. A., Koopman, P. A., Goodfellow, P. N., & Lovell-Badge, R. H. (1993) · Cell · doi:10.1016/0092-8674(93)90279-y · Cited by 1,100 · see citing works
Analysis of Intron Sequences Reveals Hallmarks of Circular RNA Biogenesis in Animals
Ivanov, A., Memczak, S., Wyler, E., Torti, F., Porath, H. T., Orejuela, M. R., Piechotta, M., Levanon, E. Y., Landthaler, M., Dieterich, C., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.12.019 · Cited by 1,092 · see citing works
Westholm, J. O., Miura, P., Olson, S., Shenker, S., Joseph, B. J., Sanfilippo, P., Celniker, S., Graveley, B. R., & Lai, E. C. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.062 · Cited by 1,001 · see citing works
miRNA‐dependent gene silencing involving Ago2‐mediated cleavage of a circular antisense RNA
Hansen, T. B., Wiklund, E. D., Bramsen, J. B., Villadsen, S. B., Statham, A. L., Clark, S. J., & Kjems, J. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.359 · Cited by 996 · see citing works
Dynamic repertoire of a eukaryotic transcriptome surveyed at single-nucleotide resolution
Wilhelm, B. T., Marguerat, S., Watt, S. B., Schubert, F., Wood, V., Goodhead, I., Penkett, C. J., Rogers, J., & Bähler, J. (2008) · Nature · doi:10.1038/nature07002 · Cited by 974 · see citing works
Short intronic repeat sequences facilitate circular RNA productionPreprint
Liang, D., & Wilusz, J. E. (2014) · Genes & Development · doi:10.1101/gad.251926.114 · Cited by 959 · see citing works
Burd, C. E., Jeck, W. R., Liu, Y., Sanoff, H. K., Wang, Z., & Sharpless, N. E. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001233 · Cited by 895 · see citing works
Nigro, J. M., Cho, K. R., Fearon, E. R., Kern, S. E., Ruppert, J. M., Oliner, J., Kinzler, K. W., & Vogelstein, B. (1991) · Cell · doi:10.1016/0092-8674(91)90244-s · Cited by 888 · see citing works
Exon Circularization Requires Canonical Splice Signals
Starke, S., Jost, I., Roßbach, O., Schneider, T. P., Schreiner, S., Hung, L.-H., & Bindereif, A. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.12.002 · Cited by 768 · see citing works
Initiation of Protein Synthesis by the Eukaryotic Translational Apparatus on Circular RNAs
Chen, C.-Y., & Sarnow, P. (1995) · Science · doi:10.1126/science.7536344 · Cited by 766 · see citing works
Widespread A-to-I RNA Editing of Alu-Containing mRNAs in the Human Transcriptome
Athanasiadis, A., Rich, A. S., & Maas, S. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020391 · Cited by 743 · see citing works
Efficient backsplicing produces translatable circular mRNAs
Wang, Y., & Wang, Z. (2014) · RNA · doi:10.1261/rna.048272.114 · Cited by 665 · see citing works
The hepatitis delta (δ) virus possesses a circular RNA
Kos, A., Dijkema, R., Arnberg, A. C., van der Meide, P. H., & Schellekens, H. (1986) · Nature · doi:10.1038/323558a0 · Cited by 651 · see citing works
Widespread RNA Editing of EmbeddedAluElements in the Human TranscriptomePreprint
Kim, D. D. Y., Kim, T. T. Y., Walsh, T., Kobayashi, Y., Matise, T. C., Buyske, S. G., & Gabriel, A. (2004) · Genome Research · doi:10.1101/gr.2855504 · Cited by 534 · see citing works
Circular RNAs: splicing’s enigma variations
Hentze, M. W., & Preiss, T. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.53 · Cited by 455 · see citing works
Genomewide characterization of non-polyadenylated RNAs
Yang, L. C., Duff, M. O., Graveley, B. R., Carmichael, G., & Chen, L. (2011) · Genome biology · doi:10.1186/gb-2011-12-2-r16 · Cited by 423 · see citing works
Self-citationRbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges
Lovci, M. T., Ghanem, D., Marr, H., Arnold, J., Gee, S., Parra, M., Liang, T. Y., Stark, T. J., Gehman, L. T., Hoon, S., et al. (2013) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2699 · Cited by 385 · see citing works
Splicing with inverted order of exons occurs proximal to large introns.
Cocquerelle, C., Daubersies, P., Majérus, M.-A., Kerckaert, J. P., & Bailleul, B. (1992) · The EMBO Journal · doi:10.1002/j.1460-2075.1992.tb05148.x · Cited by 314 · see citing works
Some yeast mitochondrial RNAs are circular
Arnberg, A. C., van Ommen, G. B., Grivell, L. A., Bruggen, E. F. J. V., & Borst, P. (1980) · Cell · doi:10.1016/0092-8674(80)90505-x · Cited by 234 · see citing works
Exon circularization in mammalian nuclear extracts.
Pasman, Z., Been, M. D., & García-Blanco, M. A. (1996) · PubMed · Cited by 185 · see citing works
RNomics in Archaea reveals a further link between splicing of archaeal introns and rRNA processing
Tang, T. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.4.921 · Cited by 144 · see citing works
Chen, L., & Carmichael, G. (2008) · Cell Cycle · doi:10.4161/cc.7.21.6927 · Cited by 92 · see citing works
Self-citationChen, T. X., Xiang, J., Zhu, S., Chen, S., Yin, Q.-F., Zhang, X.-O., Zhang, J., Feng, H., Dong, R., Li, X.-J., et al. (2015) · Cell Research · doi:10.1038/cr.2015.24 · Cited by 91 · see citing works
Self-citationIntrons excised from the Delta primary transcript are localized near sites of Delta transcription.
Kopczynski, C., & Muskavitch, M. A. T. (1992) · The Journal of Cell Biology · doi:10.1083/jcb.119.3.503 · Cited by 79 · see citing works
A spliced intron accumulates as a lariat in the nucleus of T cells
Qian, L., Vu, M. N., Carter, M., & Wilkinson, M. F. (1992) · Nucleic Acids Research · doi:10.1093/nar/20.20.5345 · Cited by 78 · see citing works
Graveley, B. R. (2008) · Nature · doi:10.1038/4531197b · Cited by 61 · see citing works
Flores, R., Navarro, J. A., de la Peña, M., et al. (1999) · Biological Chemistry · doi:10.1515/bc.1999.104 · Cited by 28 · see citing works
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Sorted by citations
Circular RNA: a new star of noncoding RNAs
Qu, S., Yang, X., Li, X., Wang, J., Gao, Y., Shang, R., Sun, W., Dou, K., & Li, H. (2015) · Cancer Letters · doi:10.1016/j.canlet.2015.06.003 · Cited by 1,808 · see citing works
Engineering circular RNA for potent and stable translation in eukaryotic cells
Wesselhoeft, R. A., Kowalski, P. S., & Anderson, D. G. (2018) · Nature Communications · doi:10.1038/s41467-018-05096-6 · Cited by 884 · see citing works
mRNA-based cancer therapeutics
Liu, C., Shi, Q., Huang, X., Koo, S., Kong, N., & Tao, W. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-023-00586-2 · Cited by 500 · see citing works
RNA Circularization Diminishes Immunogenicity and Can Extend Translation Duration In Vivo
Wesselhoeft, R. A., Kowalski, P. S., Parker-Hale, F. C., Huang, Y., Bisaria, N., & Anderson, D. G. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.02.015 · Cited by 482 · see citing works
Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential
Gan, H., Lei, Y., Yuan, N., Tang, K., Hao, W., Ma, Q., Wu, M., Zhou, X., Li, X., Huang, J., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111244 · Cited by 41 · see citing works
Song, R., Bai, Y., Li, X., Zhu, J., Zhang, H., Shi, Y., Li, K., Wang, B., Zhang, H., Yang, Y., et al. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.05.109 · Cited by 37 · see citing works
- Authors
- Chen, L.-L., & Yang, L.
- Affiliations
- Chinese Academy of Sciences (CN)
- Corresponding author
- Chen, Ling-Ling
- Yang, Li
- Venue
- RNA Biology
- Publisher
- Informa UK Limited
- Published
- 2015-03-06
- Volume
- 12
- Issue
- 4
- Pages
- 381-388
- ISSN
- 1547-6286 (ISSN-L)
- 1555-8584
- PMC
- PMC4615371
- OpenAlex
- W2302185643
- Cited by
- 1,953
- References
- 42
- Citations by year
- 2026: 60 · 2025: 110 · 2024: 196 · 2023: 203 · 2022: 333 · 2021: 368 · 2020: 305 · 2019: 153 · 2018: 128 · 2017: 57 · 2016: 28 · 2015: 10
- FWCI
- 32.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- RNA Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (31471241, 31322018, 91440202)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- circular RNA, circRNA biogenesis, back-splicing, spliceosome, RNA circularization
- MeSH terms
- RNA, Circular, Humans, Regulatory Sequences, Nucleic Acid, RNA, RNA Precursors, RNA Splicing
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