The DOI matches its Crossref record; 40 of the 41 references it cites were found in a registry or an index.
Circular RNAs are abundant, conserved, and associated with ALU repeats
Open accessAbstract
Circular RNAs composed of exonic sequence have been described in a small number of genes. Thought to result from splicing errors, circular RNA species possess no known function. To delineate the universe of endogenous circular RNAs, we performed high-throughput sequencing (RNA-seq) of libraries prepared from ribosome-depleted RNA with or without digestion with the RNA exonuclease, RNase R. We identified >25,000 distinct RNA species in human fibroblasts that contained non-colinear exons (a "backsplice") and were reproducibly enriched by exonuclease degradation of linear RNA. These RNAs were validated as circular RNA (ecircRNA), rather than linear RNA, and were more stable than associated linear mRNAs in vivo. In some cases, the abundance of circular molecules exceeded that of associated linear mRNA by >10-fold. By conservative estimate, we identified ecircRNAs from 14.4% of actively transcribed genes in human fibroblasts. Application of this method to murine testis RNA identified 69 ecircRNAs in precisely orthologous locations to human circular RNAs. Of note, paralogous kinases HIPK2 and HIPK3 produce abundant ecircRNA from their second exon in both humans and mice. Though HIPK3 circular RNAs contain an AUG translation start, it and other ecircRNAs were not bound to ribosomes. Circular RNAs could be degraded by siRNAs and, therefore, may act as competing endogenous RNAs. Bioinformatic analysis revealed shared features of circularized exons, including long bordering introns that contained complementary ALU repeats. These data show that ecircRNAs are abundant, stable, conserved and nonrandom products of RNA splicing that could be involved in control of gene expression.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Two different models of circRNA formation have been proposed: an exon-skipping process known as “Lariat-Driven Circularization” and a nonsequential donor-acceptor pairing process called “Intron-Pairing-Driven Circularization” or “direct back splicing” [28].”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [28]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Single-Step Method of RNA Isolation by Acid Guanidinium Thiocyanate–Phenol–Chloroform Extraction
Chomczynski, P., & Sacchi, N. (1987) · Analytical Biochemistry · doi:10.1006/abio.1987.9999 · Cited by 65,515
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.211 · Cited by 35,890
BEDTools: a flexible suite of utilities for comparing genomic features
Quinlan, A. R., & Hall, I. M. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq033 · Cited by 27,437
Robinson, J. T., Thorvaldsdóttir, H., Winckler, W., Guttman, M., Lander, E. S., Getz, G., & Mesirov, J. P. (2011) · Nature Biotechnology · doi:10.1038/nbt.1754 · Cited by 15,390
Non-coding RNAs in human disease
Esteller, M. (2011) · Nature Reviews Genetics · doi:10.1038/nrg3074 · Cited by 4,825
Argonaute2 is the catalytic engine of mammalian RNAi
Liu, J., Carmell, M. A., Rivas, F. V., Marsden, C. G., Thomson, J. M., Song, J.-J., Hammond, S. M., Joshua-Tor, L., & Hannon, G. J. (2004) · Science · doi:10.1126/science.1102513 · Cited by 2,796
Self-citationA coding-independent function of gene and pseudogene mRNAs regulates tumour biology
Poliseno, L., Salmena, L., Zhang, J., Carver, B. S., Haveman, W. J., & Pandolfi, P. P. (2010) · Nature · doi:10.1038/nature09144 · Cited by 2,364
Salzman, J., Gawad, C., Wang, P. L., Lacayo, N., & Brown, P. O. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030733 · Cited by 2,239
MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells
Ebert, M. S., Neilson, J. R., & Sharp, P. A. (2007) · Nature Methods · doi:10.1038/nmeth1079 · Cited by 2,108
Target mimicry provides a new mechanism for regulation of microRNA activity
Franco‐Zorrilla, J. M., Valli, A. A., Todesco, M., Mateos, I., Puga, M. I., Rubio‐Somoza, I., Leyva, A., Weigel, D., Garcı́a, J. A., & Paz‐Ares, J. (2007) · Nature Genetics · doi:10.1038/ng2079 · Cited by 2,101
Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs
Meister, G., Landthaler, M., Patkaniowska, A., Dorsett, Y., Teng, G., & Tuschl, T. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.07.007 · Cited by 2,052
The economics of ribosome biosynthesis in yeast
Warner, J. R. (1999) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(99)01460-7 · Cited by 1,933
Pre-mRNA splicing and human diseasePreprint
Faustino, N. A., & Cooper, T. A. (2003) · Genes & Development · doi:10.1101/gad.1048803 · Cited by 1,248
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
MapSplice: Accurate mapping of RNA-seq reads for splice junction discovery
Wang, K., Singh, D., Zeng, Z., Coleman, S. J., Huang, Y., Savich, G. L., He, X., Mieczkowski, P., Grimm, S. A., Perou, C. M., et al. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq622 · Cited by 1,193
Self-citationCircular 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 1,112
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
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 909
Self-citationNigro, 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 906
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
Functional consequences of developmentally regulated alternative splicing
Kalsotra, A., & Cooper, T. A. (2011) · Nature Reviews Genetics · doi:10.1038/nrg3052 · Cited by 729
Suzuki, H. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl151 · Cited by 687
Transcriptome-wide discovery of circular RNAs in Archaea
Danan, M., Schwartz, S., Edelheit, S., & Sorek, R. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr1009 · Cited by 560
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 436
Human branch point consensus sequence is yUnAy
Gao, K., Masuda, A., Matsuura, T., & Ohno, K. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn073 · Cited by 284
The architecture of pre-mRNAs affects mechanisms of splice-site pairing
Fox-Walsh, K. L., Dou, Y., Lam, B. J., Hung, S., Baldi, P., & Hertel, K. J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508489102 · Cited by 267
INK4a‐deficient human diploid fibroblasts are resistant to RAS‐induced senescence
Brookes, S., Rowe, J., Ruas, M., Llanos, S., Clark, P. A., Lomax, M., James, M. C., Vatcheva, R., Bates, S., Vousden, K. H., et al. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf289 · Cited by 220
Exon circularization in mammalian nuclear extracts.
Pasman, Z., Been, M. D., & García-Blanco, M. A. (1996) · PubMed · Cited by 185
Zaphiropoulos, P. G. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.6.2985 · Cited by 177
Inverted repeats are necessary for circularization of the mouse testis Sry transcript
Dubin, R. A., Kazmi, M. A., & D, H. O. M. (1995) · Gene · doi:10.1016/0378-1119(95)00639-7 · Cited by 154
Exhaustive Search for Over-represented DNA Sequence Motifs with CisFinder
Sharov, A. A., & Ko, M. S. H. (2009) · DNA Research · doi:10.1093/dnares/dsp014 · Cited by 127
Isono, K., Mizutani-Koseki, Y., Komori, T., Schmidt-Zachmann, M. S., & Koseki, H. (2005) · Genes & Development · doi:10.1101/gad.1284605 · Cited by 110
Genome-wide analysis of mRNA lengths in Saccharomyces cerevisiae
Hurowitz, E. H., & Brown, P. O. (2003) · Genome biology · doi:10.1186/gb-2003-5-1-r2 · Cited by 107
Alternative splicing in multiple sclerosis and other autoimmune diseases
Evsyukova, I. Y., Somarelli, J. A., Gregory, S. G., & García-Blanco, M. A. (2010) · RNA Biology · doi:10.4161/rna.7.4.12301 · Cited by 83
Ganguly, A. A., Dunbar, T., Chen, P., Godmilow, L., & Ganguly, T. (2003) · Human Genetics · doi:10.1007/s00439-003-0986-5 · Cited by 80
Reverse transcriptase reads through a 2′–5′ linkage and a 2′-thiphosphate in a template
Lorsch, J. R., Bartel, D. P., & Szostak, J. W. (1995) · Nucleic Acids Research · doi:10.1093/nar/23.15.2811 · Cited by 69
Post-transcriptional exon shuffling events in humans can be evolutionarily conserved and abundantPreprint
Al‐Balool, H. H., Weber, D., Liu, Y., Wade, M., Guleria, K., Nam, P. L. P., Clayton, J., Rowe, W. P. M., Coxhead, J. M., Irving, J. A. E., et al. (2011) · Genome Research · doi:10.1101/gr.116442.110 · Cited by 46
Spliceosomes walk the line: Splicing errors and their impact on cellular function
Hsu, S.-N., & Hertel, K. J. (2009) · RNA Biology · doi:10.4161/rna.6.5.9860 · Cited by 33
Mutations in RNA Splicing Machinery in Human Cancers
Ebert, B. L., & Bernard, O. (2011) · New England Journal of Medicine · doi:10.1056/nejme1111584 · Cited by 26
Virtual Northern Analysis of the Human Genome
Hurowitz, E. H., Drori, I., Stodden, V., Donoho, D. L., & Brown, P. O. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000460 · Cited by 12
Flagged first, then by citations
1 of the 41 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
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
The biogenesis, biology and characterization of circular RNAs
Kristensen, L. S., Andersen, M. S., Stagsted, L. V. W., Ebbesen, K. K., Hansen, T. B., & Kjems, J. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0158-7 · Cited by 4,823
The multilayered complexity of ceRNA crosstalk and competition
Tay, Y., Rinn, J., & Pandolfi, P. P. (2014) · Nature · doi:10.1038/nature12986 · Cited by 3,910
Unique features of long non-coding RNA biogenesis and function
Quinn, J. J., & Chang, H. Y. (2015) · Nature Reviews Genetics · doi:10.1038/nrg.2015.10 · Cited by 3,700
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
Metadata
- Authors
- Jeck, W. R., Sorrentino, J. A., Wang, K., Slevin, M. K., Burd, C. E., Liu, J., Marzluff, W. F., & Sharpless, N. E.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- University of Kentucky (US)
- ORCID
- Venue
- RNA
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-12-18
- Volume
- 19
- Issue
- 2
- Pages
- 141-157
- ISSN
- 1355-8382 (ISSN-L)
- 1469-9001
- PMC
- PMC3543092
- OpenAlex
- W2147806662
- Cited by
- 4,388
- References
- 41
- Citations by year
- 2026: 165 · 2025: 251 · 2024: 369 · 2023: 409 · 2022: 566 · 2021: 655 · 2020: 612 · 2019: 467 · 2018: 369 · 2017: 227 · 2016: 121 · 2015: 92 · 2014: 47 · 2013: 31 · 2012: 1
- FWCI
- 22.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- RNA (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- UNC Libraries
- Funders
- Glenn Foundation for Medical Research
- National Institutes of Health (5r01ag024379-15)
- National Institute on Aging (AG024379, AG041567, R01-AG024379, F30AG041567)
- National Human Genome Research Institute (R01HG006272)
- National Institute of General Medical Sciences (F32GM087059, T32GM007092)
- National Institute of Environmental Health Sciences (T32ES007126)
- 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 › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- circular RNA, back-splicing, Alu elements, RNase R, human fibroblasts, mouse testis, HIPK2, HIPK3, competing endogenous RNA, RNA stability, gene expression regulation
- MeSH terms
- RNA, Circular, Animals, Base Sequence, Cells, Cultured, Exons, Exoribonucleases, Gene Expression Regulation, Humans, Male, Molecular Sequence Data, Phosphotransferases, RNA, RNA Splicing, Conserved Sequence, Sequence Analysis, RNA, Evolution, Molecular, Computational Biology, Trans-Splicing, Alu Elements, RNA Stability, RNA, Small Interfering, Mice, High-Throughput Nucleotide Sequencing, Nucleotide Motifs
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
