Circular RNAs: molecules with past and future

Authors

DOI:

https://doi.org/10.17533/udea.acbi.v44n117a03

Keywords:

ALU sequence , backsplicing, miRNA sponge

Abstract

Circular RNAs (circRNAs) are a class of recently identified RNAs highly expressed in eukaryotes and conservedbetween species. The biogenesis of circRNAs is a product of the backsplicing process that occurs duringpre‐mRNA maturation, where the binding 3’ donor and 5’ acceptor sites produce a circular molecule.The closed loop structure of circRNAs provides greater stability and increases resistance to the activityof some RNAses when compared to linear RNA. Different functions of circRNAs have been postulated suchas splicing competition against the gene from which they derive, miRNA sponges, regulators of CpG islandmethylation, or mediators in pAKT migration to the nucleus. Therefore, circRNAs are considered importantpost‐transcriptional regulators for cell survival and have been used as biomarkers in cancer diseases. Theabundance of circRNA in neural tissue also implicates them in the development of different nervous systempathologies including those found in geriatric patients. The aim of this review is to summarize the currentknowledge of circRNAs in eukaryotes by presenting possible functions and highlighting their importance incardiac, nervous, endocrine, and digestive systems. Moreover, the impact on cardiogenesis, neurodegenera tion, and cancer are discussed to understand why circRNAs are considered as an important tool in molecularbiology research field.
 
 
|Abstract
= 1521 veces | PDF
= 491 veces| | HTML
= 26 veces| | XML
= 10 veces|

Downloads

Download data is not yet available.

Author Biographies

Karol Andrea Arizaca Maquera , Leloir Institute Foundation 

RNA Biology Laboratory, Leloir Institute Foundation (FIL), Buenos Aires, Argentina

Ana Julia Fernández Álvarez, Leloir Institute Foundation

RNA Biology Laboratory, Leloir Institute Foundation (FIL), Buenos Aires, Argentina.

References

Akhter, R. (2018). Circular RNA and Alzheimer’s Disease.Advances in Experimental Medicine and Biology, 1087,239–243. DOI:10.1007/978-981-13-1426-119

Ashwal-Fluss, R., Meyer, M., Pamudurti, N. R., Ivanov, A.,Bartok, O., Hanan, M., Evantal, N., Memczak, S., Rajew-sky, N., & Kadener, S. (2014). circRNA biogenesis com-petes with pre-mRNA splicing.Molecular Cell, 56(1),55–66. DOI:10.1016/j.molcel.2014.08.019

Aufiero, S., Reckman, Y. J., Tijsen, A. J., Pinto, J. M., &Creemers, E. E. (2020). circRNAprofiler: An R-basedcomputational framework for the downstream analy-sis of circular RNAs.BMC Bioinformatics, 21, 164DOI:10.1186/s12859-020-3500-3

Bachmayr-Heyda, A., Reiner, A. T., Auer, K., Sukhbaatar, N.,Aust, S., Bachleitner-Hofmann, T., Mesteri, I., Grunt, T.W., Zeillinger, R., & Pils, D. (2015). Correlation of circu-lar RNA abundance with proliferation-exemplified withcolorectal and ovarian cancer, idiopathic lung fibrosis,and normal human tissues.Scientific Reports, 5, 8057.DOI:10.1038/srep08057

Chen, L. L., & Carmichael, G. G. (2008). Gene reg-ulation by SINES and inosines: Biological conse-quences of A-to-I editing of Alu element inverted re-peats.Cell cycle (Georgetown, Tex.), 7(21), 3294–3301DOI:10.4161/cc.7.21.6927

Choi, D. C., Chae, Y. J., Kabaria, S., Chaudhuri, A. D.,Jain, M. R., Li, H., Mouradian, M. M., & Junn,E. (2014). MicroRNA-7 protects against 1-methyl-4-phenylpyridinium-induced cell death by targeting RelA.The Journal of Neuroscience: The Official Journalof the Society for Neuroscience, 34(38), 12725–12737.DOI:10.1523/JNEUROSCI.0985-14.2014

Cocquerelle, C., Daubersies, P., Maj ́erus, M. A., Kerckaert,J. P., & Bailleul, B. (1992). Splicing with invertedorder of exons occurs proximal to large introns.TheEMBO Journal, 11(3), 1095–1098. DOI:10.1002/j.1460-2075.1992.tb05148.x

Cocquerelle, C., Mascrez, B., H ́etuin, D., & Bailleul, B. (1993).Mis-splicing yields circular RNA molecules.FASEB jour-nal: official publication of the Federation of Ameri-can Societies for Experimental Biology, 7(1), 155–160.DOI:10.1096/fasebj.7.1.7678559

Conn, S. J., Pillman, K. A., Toubia, J., Conn, V. M., Salmani-dis, M., Phillips, C. A., Roslan, S., Schreiber, A. W., Gre-gory, P. A., & Goodall, G. J. (2015). The RNA bindingprotein quaking regulates formation of circRNAs.Cell,160(6), 1125–1134. DOI:10.1016/j.cell.2015.02.014

Cortés-López, M., Gruner, M. R., Cooper, D. A., Gruner, H.N., Voda, A. I., van der Linden, A. M., & Miura, P.(2018). Global accumulation of circRNAs during aging inCaenorhabditis elegans.BMC genomics, 19(1), 8. DOI:10.1186/s12864-017-4386-y

Du, W. W., Yang, W., Liu, E., Yang, Z., Dhaliwal, P., &Yang, B. B. (2016). Foxo3 circular RNA retards cell cycleprogression via forming ternary complexes with p21 andCDK2.Nucleic Acids Research, 44(6), 2846–2858. DOI:10.1093/nar/gkw027

Du, W. W., Yang, W., Chen, Y., Wu, Z. K., Foster, F. S.,Yang, Z., Li, X., & Yang, B. B. (2017). Foxo3 circu-lar RNA promotes cardiac senescence by modulatingmultiple factors associated with stress and senescenceresponses.European Heart Journal, 38(18), 1402–1412.DOI:10.1093/eurheartj/ehw001

Dubin, R. A., Kazmi, M. A., & Ostrer, H. (1995). Invertedrepeats are necessary for circularization of the mousetestis Sry transcript.Gene, 167(1-2), 245–248. DOI:10.1016/0378-1119(95)00639-7

Dudekula, D. B., Panda, A. C., Grammatikakis, I., De, S., Ab-delmohsen, K., & Gorospe, M. (2016). CircInteractome:A web tool for exploring circular RNAs and their interact-ing proteins and microRNAs.RNA Biology, 13(1), 34–42.DOI:10.1080/15476286.2015.1128065

Errichelli, L., Dini Modigliani, S., Laneve, P., Colantoni,A., Legnini, I., Capauto, D., Rosa, A., De Santis, R.,Scarf`o, R., Peruzzi, G., Lu, L., Caffarelli, E., Shneider,N. A., Morlando, M., & Bozzoni, I. (2017). FUS af-fects circular RNA expression in murine embryonic stemcell-derived motor neurons.Nature Communications, 8,14741. DOI:10.1038/ncomms14741

Geng, H. H., Li, R., Su, Y. M., Xiao, J., Pan, M., Cai, X. X., &Ji, X. P. (2016). The circular RNA Cdr1 as promotes my-ocardial infarction by mediating the regulation of miR-7aon its target genes expression.PloS One, 11(3), e0151753.DOI:10.1371/journal.pone.0054063

Gruner, H., Cort ́es-L ́opez, M., Cooper, D. A., Bauer,M., Miura, P. (2016). CircRNA accumulation inthe aging mouse brain.Scientific Reports, 6, 38907.DOI:10.1038/srep38907

Hansen, T. B., Jensen, T. I., Clausen, B. H., Bramsen, J. B.,Finsen, B., Damgaard, C. K., & Kjems, J. (2013). NaturalRNA circles function as efficient microRNA sponges.Nature, 495(7441), 384–388. DOI:10.1038/nature11993

Huang, C., Liang, D., Tatomer, D. C., & Wilusz, J. E. (2018). Alength-dependent evolutionarily conserved pathway con-trols nuclear export of circular RNAs.Genes&Develop-ment, 32(9-10), 639–644. DOI:10.1101/gad.314856.118

Ivanov, A., Memczak, S., Wyler, E., Torti, F., Porath, H.T., Orejuela, M. R., Piechotta, M., Levanon, E. Y., Landthaler, M., Dieterich, C., & Rajewsky, N. (2015).Analysis of intron sequences reveals hallmarks of circularRNA biogenesis in animals.Cell Reports, 10(2), 170–177.DOI:10.1016/j.celrep.2014.12.019

Jakobi, T., & Dieterich, C. (2019). Computational approachesfor circular RNA analysis.Wiley Interdisciplinary Re-views. RNA, 10(3), e1528. DOI:10.1002/wrna.1528

Jeck, W. R., & Sharpless, N. E. (2014). Detecting and char-acterizing circular RNAs.Nature Biotechnology, 32(5),453–461. DOI:10.1038/nbt.2890

Jeck, W. R., Sorrentino, J. A., Wang, K., Slevin, M. K.,Burd, C. E., Liu, J., Marzluff, W. F., & Sharpless,N. E. (2013). Circular RNAs are abundant, conserved,and associated with ALU repeats.RNA, 19(2), 141–157.DOI:10.1261/rna.035667.112

Jia, R., Xiao, M. S., Li, Z., Shan, G., & Huang, C. (2019).Defining an evolutionarily conserved role of GW182in circular RNA degradation.Cell Discovery, 5, 45.DOI:10.1038/s41421-019-0113-y

Junn, E., Lee, K. W., Jeong, B. S., Chan, T. W., Im,J. Y., & Mouradian, M. M. (2009). Repression ofalpha-synuclein expression and toxicity by microRNA-7.Proceedings of the National Academy of Sciences ofthe United States of America, 106(31), 13052–13057.DOI:10.1073/pnas.0906277106

Kornblihtt, A. R., Schor, I. E., All ́o, M., Dujardin, G., Petrillo,E., & Mu ̃noz, M. J. (2013). Alternative splicing: A pivotalstep between eukaryotic transcription and translation.Nature Reviews. Molecular Cell Biology, 14(3), 153–165.DOI:10.1038/nrm3525

Kos, A., Dijkema, R., Arnberg, A. C., van der Meide, P.H., & Schellekens, H. (1986). The hepatitis delta viruspossesses a circular RNA.Nature, 323(6088), 558–560.DOI:10.1038/323558a0

Kreahling, J., & Graveley, B. R. (2004). The origins and impli-cations of alternative splicing.Trends in Genetics, 20(1),1–4. DOI:10.1016/j.tig.2003.11.001

Lee, E., Elhassan, S., Lim, G., Kok, W. H., Tan, S. W.,Leong, E. N., Tan, S. H., Chan, E., Bhattamisra,S. K., Rajendran, R.,& Candasamy, M. (2019). Theroles of circular RNAs in human development anddiseases.Biomedicine pharmacotherapy, 111, 198–208.DOI:10.1016/j.biopha.2018.12.052

Li, Z., Huang, C., Bao, C., Chen, L., Lin, M., Wang, X., Zhong,G., Yu, B., Hu, W., Dai, L., Zhu, P., Chang, Z., Wu,Q., Zhao, Y., Jia, Y., Xu, P., Liu, H., Shan, G. (2015).Exon-intron circular RNAs regulate transcription in thenucleus.Nature Structural Molecular Biology, 22(3),256–264. DOI:10.1038/nsmb.2959

Li, Z., Kearse, M. G.,& Huang, C. (2019). The nuclear export of circular RNAs is primarily de-fined by their length.RNA Biology, 16(1), 1–4.DOI:10.1080/15476286.2018.1557498

Liu, B. H., Zhang, B. B., Liu, X. Q., Zheng, S., Dong, K. R.,&Dong, R. (2018). Expression profiling identifies circularRNA signature in hepatoblastoma.International Journalof Experimental Cellular Physiology, Biochemistry, andPharmacology, 45(2), 706–719. DOI:10.1159/000487163

Lukiw, W. J. (2013). Circular RNA (circRNA) inAlzheimer’s disease (AD).Frontiers in Genetics, 4,307. DOI:10.3389/fgene.2013.00307

Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J.,Rybak, A., Maier, L., Mackowiak, S. D., Gregersen, L.H., Munschauer, M., Loewer, A., Ziebold, U., Landthaler,M., Kocks, C., le Noble, F., & Rajewsky, N. (2013).Circular RNAs are a large class of animal RNAs withregulatory potency.Nature, 495(7441), 333–338. DOI:10.1038/nature11928

Niaz, S., & Hussain, M. U. (2018). Role of GW182 protein inthe cell.The International Journal of Biochemistry CellBiology, 101, 29–38. DOI:10.1016/j.biocel.2018.05.009

Ning, S., Wei, W., Li, J., Hou, B., Zhong, J., Xie, Y., Liu,H., Mo, X., Chen, J., & Zhang, L. (2018). Clinical sig-nificance and diagnostic capacity of serum TK1, CEA,CA 19-9 and CA 72-4 levels in gastric and colorec-tal cancer patients.Journal of Cancer, 9(3), 494–501.DOI:10.7150/jca.21562

Nishikura K. (2010). Functions and regulation of RNA edit-ing by ADAR deaminases.Annual Review of Bio-chemistry, 79, 321–349. DOI:10.1146/annurev-biochem-060208-105251

Pamudurti, N. R., Bartok, O., Jens, M., Ashwal-Fluss,R., Stottmeister, C., Ruhe, L., Hanan, M., Wyler,E., Perez-Hernandez, D., Ramberger, E., Shenzis, S.,Samson, M., Dittmar, G., Landthaler, M., Cheku-laeva, M., Rajewsky, N., & Kadener, S. (2017). Trans-lation of CircRNAs.Molecular Cell, 66(1), 9–21.e7.DOI:10.1016/j.molcel.2017.02.021

Patop, I. L., W ̈ust, S., & Kadener, S. (2019). Past, present,and future of circRNAs.The EMBO Journal, 38, (16),e100836. DOI:10.15252/embj.2018100836

Rybak-Wolf, A., Stottmeister, C., Glaar, P., Jens, M., Pino, N.,Giusti, S., Hanan, M., Behm, M., Bartok, O., Ashwal-Fluss, R., Herzog, M., Schreyer, L., Papavasileiou, P.,Ivanov, A., ̈Ohman, M., Refojo, D., Kadener, S., &Rajewsky, N. (2015). Circular RNAs in the mammalianbrain are highly abundant, conserved, and dynami-cally expressed.Molecular Cell, 58(5), 870–885. DOI:10.1016/j.molcel.2015.03.027

Salgia, S. R., Singh, S. K., Gurha, P., & Gupta, R. (2003). Tworeactions of Haloferax volcanii RNA splicing enzymes:Joining of exons and circularization of introns.RNA,9(3), 319–330. DOI:10.1261/rna.2118203

Salzman, J., Gawad, C., Wang, P. L., Lacayo, N., &Brown, P. O. (2012). Circular RNAs are the pre-dominant transcript isoform from hundreds of humangenes in diverse cell types.PloS One, 7(2), e30733.DOI:10.1371/journal.pone.0030733

Sang, Q., Liu, X., Wang, L., Qi, L., Sun, W., Wang, W.,Sun, Y., & Zhang, H. (2018). CircSNCA downregulationby pramipexole treatment mediates cell apoptosis andautophagy in Parkinson’s disease by targeting miR-7.Aging, 10(6), 1281–1293. DOI:10.18632/aging.101466

Sanger, H. L., Klotz, G., Riesner, D., Gross, H. J., & Klein-schmidt, A. K. (1976). Viroids are single-stranded cova-lently closed circular RNA molecules existing as highlybase-paired rod-like structures.Proceedings of the Na-tional Academy of Sciences of the United States of Amer-ica, 73(11), 3852–3856. DOI:10.1073/pnas.73.11.3852

Shao, Y., & Chen, Y. (2016). Roles of Circular RNAs in neurologic disease.Frontiers in molecular neuroscience,9, 25. DOI:10.3389/fnmol.2016.00025

Sun, X., Wang, L., Ding, J., Wang, Y., Wang, J., Zhang, X.,Che, Y., Liu, Z., Zhang, X., Ye, J., Wang, J., Sablok,G., Deng, Z., & Zhao, H. (2016). Integrative analysisofArabidopsis thalianatranscriptomics reveals intuitivesplicing mechanism for circular RNA.FEBS Letters,590(20), 3510–3516. DOI:10.1002/1873-3468.12440

Suzuki, H., Zuo, Y., Wang, J., Zhang, M. Q., Malhotra, A.,& Mayeda, A. (2006). Characterization of RNase R-digested cellular RNA source that consists of lariat andcircular RNAs from pre-mRNA splicing.Nucleic AcidsResearch, 34(8), e63. DOI:10.1093/nar/gkl151

Taibi, F., Metzinger-Le Meuth, V., Massy, Z. A., & Metzinger,L. (2014). miR-223: An inflammatory oncomiR entersthe cardiovascular field.Biochimica et Biophysica Acta,1842(7), 1001–1009. DOI:10.1016/j.bbadis.2014.03.005

Venø, M. T., Hansen, T. B., Venø, S. T., Clausen, B. H.,Grebing, M., Finsen, B., Holm, I. E., & Kjems, J. (2015).Spatio-temporal regulation of circular RNA expressionduring porcine embryonic brain development.GenomeBiology, 16, 245. DOI:10.1186/s13059-015-0801-3

Welden, J. R., van Doorn, J., Nelson, P. T., & Stamm,S. (2018). The human MAPT locus generates cir-cular RNAs.Biochimica et Biophysica Acta. Molec-ular Basis of Disease, 1864(9 Pt B), 2753–2760.DOI:10.1016/j.bbadis.2018.04.023

Westholm, J. O., Miura, P., Olson, S., Shenker, S., Joseph, B.,Sanfilippo, P., Celniker, S. E., Graveley, B. R., & Lai, E.C. (2014). Genome-wide analysis ofDrosophilacircularRNAs reveals their structural and sequence propertiesand age-dependent neural accumulation.Cell Reports,9(5), 1966–1980. DOI:10.1016/j.celrep.2014.10.062

Xu Y. (2017). An overview of the main circRNAdatabases.Non-coding RNA Investigation, 1(4), 22–26.DOI:10.21037/ncri.2017.11.05

Ye, C. Y., Chen, L., Liu, C., Zhu, Q. H., & Fan, L. (2015).Widespread noncoding circular RNAs in plants.The NewPhytologist, 208(1), 88–95. DOI:10.1111/nph.13585

You, X., Vlatkovic, I., Babic, A., Will, T., Epstein, I., Tushev,G., Akbalik, G., Wang, M., Glock, C., Quedenau, C.,Wang, X., Hou, J., Liu, H., Sun, W., Sambandan, S.,Chen, T., Schuman, E. M., & Chen, W. (2015). Neu-ral circular RNAs are derived from synaptic genes andregulated by development and plasticity.Nature Neuro-science, 18(4), 603–610. DOI:10.1038/nn.3975

Yu, C. Y., Li, T. C., Wu, Y. Y., Yeh, C. H., Chiang, W.,Chuang, C. Y., & Kuo, H. C. (2017). The circular RNAcircBIRC6 participates in the molecular circuitry control-ling human pluripotency.Nature Communications, 8(1),1149. DOI:10.1038/s41467-017-01216-w

Zeng, Y., Du, W. W., Wu, Y., Yang, Z., Awan, F. M., Li,X., Yang, W., Zhang, C., Yang, Q., Yee, A., Chen,Y., Yang, F., Sun, H., Huang, R., Yee, A. J., Li, R.K., Wu, Z., Backx, P. H., & Yang, B. B. (2017). ACircular RNA binds to and activates AKT phosphory-lation and nuclear localization reducing apoptosis andenhancing cardiac repair.Theranostics, 7(16), 3842–3855.DOI:10.7150/thno.19764

Zhang, Y., Zhang, X. O., Chen, T., Xiang, J. F., Yin, Q. F.,Xing, Y. H., Zhu, S., Yang, L., & Chen, L. L. (2013).Circular intronic long noncoding RNAs.Molecular Cell,51(6), 792–806. DOI:10.1016/j.molcel.2013.08.017

Zheng, Q., Bao, C., Guo, W., Li, S., Chen, J., Chen, B.,Luo, Y., Lyu, D., Li, Y., Shi, G., Liang, L., Gu, J., He,X., & Huang, S. (2016). Circular RNA profiling revealsan abundant circHIPK3 that regulates cell growth bysponging multiple miRNAs.Nature Communications, 7,11215. DOI:10.1038/ncomms1121512

Downloads

Published

2022-04-26

How to Cite

Arizaca Maquera, K. A., & Fernández-Álvarez, A. J. (2022). Circular RNAs: molecules with past and future. Actualidades Biológicas, 44(117), 1–12. https://doi.org/10.17533/udea.acbi.v44n117a03

Issue

Vol. 44 No. 117 (2022)

Section

Review articles

License

Copyright (c) 2022 Actualidades Biológicas

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

The authors exclusively authorize the Actualidades Biológicas journal to edit and publish the submitted manuscript if its publication is recommended and accepted, without this representing any cost to the Journal or the University of Antioquia.

All the ideas and opinions contained in the articles are sole responsibility of the authors. The total content of the issues or supplements of the journal is protected under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License, so they cannot be used for commercial purposes, but for educational purposes. However, please mention the Actualidades Biológicas journal as a source and send a copy of the publication in which the content was reproduced.

Crossref
Scopus
Google Scholar
Europe PMC