Cited by 4,388Circular RNAs in diseasesRNA Research and SplicingCancer-related molecular mechanisms research

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Circular RNAs are abundant, conserved, and associated with ALU repeats

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Jeck, William R., Sorrentino, Jessica A., Wang, Kai, Slevin, Michael K., Burd, Christin E., Liu, Jinze, Marzluff, William F., Sharpless, Norman E.·2013·RNA

DOI 10.1261/rna.035667.112PMC PMC3543092

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Abstract

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.

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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: Jeck, William R.
Sorrentino, Jessica A.
Slevin, Michael K.
Burd, Christin E.
Liu, Jinze
Marzluff, William F.
Sharpless, Norman E.
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
DOI: 10.1261/rna.035667.112
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

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Circular RNAs are abundant, conserved, and associated with ALU repeats

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