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      Circular RNAs in cell cycle regulation: Mechanisms to clinical significance

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          Abstract

          Circular RNAs (circRNAs), a type of non‐coding RNA, are single‐stranded circularized molecules characterized by high abundance, evolutionary conservation and cell development‐ and tissue‐specific expression. A large body of studies has found that circRNAs exert a wide variety of functions in diverse biological processes, including cell cycle. The cell cycle is controlled by the coordinated activation and deactivation of cell cycle regulators. CircRNAs exert mutifunctional roles by regulating gene expression via various mechanisms. However, the functional relevance of circRNAs and cell cycle regulation largely remains to be elucidated. Herein, we briefly describe the biogenesis and mechanistic models of circRNAs and summarize their functions and mechanisms in the regulation of critical cell cycle modulators, including cyclins, cyclin‐dependent kinases and cyclin‐dependent kinase inhibitors. Moreover, we highlight the participation of circRNAs in cell cycle‐related signalling pathways and the clinical value of circRNAs as promising biomarkers or therapeutic targets in diseases related to cell cycle disorder.

          Abstract

          CircRNAs exert a wide variety of functions in diverse biological processes, including cell cycle. The cell cycle is controlled by the coordinated activation and deactivation of cell cycle regulators, including cyclins, cyclin‐dependent kinases and cyclin‐dependent kinase inhibitors. This review summarizes the functions and mechanisms of circRNAs in cell cycle regulation and highlights the clinical value of circRNAs as promising biomarkers or therapeutic targets.

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          Most cited references126

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          The biogenesis, biology and characterization of circular RNAs

          Circular RNAs (circRNAs) are covalently closed, endogenous biomolecules in eukaryotes with tissue-specific and cell-specific expression patterns, whose biogenesis is regulated by specific cis-acting elements and trans-acting factors. Some circRNAs are abundant and evolutionarily conserved, and many circRNAs exert important biological functions by acting as microRNA or protein inhibitors ('sponges'), by regulating protein function or by being translated themselves. Furthermore, circRNAs have been implicated in diseases such as diabetes mellitus, neurological disorders, cardiovascular diseases and cancer. Although the circular nature of these transcripts makes their detection, quantification and functional characterization challenging, recent advances in high-throughput RNA sequencing and circRNA-specific computational tools have driven the development of state-of-the-art approaches for their identification, and novel approaches to functional characterization are emerging.
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            Circular RNAs are abundant, conserved, and associated with ALU repeats.

            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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              The multilayered complexity of ceRNA crosstalk and competition.

              Recent reports have described an intricate interplay among diverse RNA species, including protein-coding messenger RNAs and non-coding RNAs such as long non-coding RNAs, pseudogenes and circular RNAs. These RNA transcripts act as competing endogenous RNAs (ceRNAs) or natural microRNA sponges - they communicate with and co-regulate each other by competing for binding to shared microRNAs, a family of small non-coding RNAs that are important post-transcriptional regulators of gene expression. Understanding this novel RNA crosstalk will lead to significant insight into gene regulatory networks and have implications in human development and disease.
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                Author and article information

                Contributors
                huangjr999@sina.com
                phcgs@nus.edu.sg
                mazw@yangtzeu.edu.cn
                Journal
                Cell Prolif
                Cell Prolif
                10.1111/(ISSN)1365-2184
                CPR
                Cell Proliferation
                John Wiley and Sons Inc. (Hoboken )
                0960-7722
                1365-2184
                20 October 2021
                December 2021
                : 54
                : 12 ( doiID: 10.1111/cpr.v54.12 )
                : e13143
                Affiliations
                [ 1 ] Health Science Center Yangtze University Jingzhou China
                [ 2 ] Key Laboratory of Environmental Health Ministry of Education Department of Toxicology School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China
                [ 3 ] The Second School of Clinical Medicine Yangtze University Jingzhou China
                [ 4 ] Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
                [ 5 ] Cancer Science Institute of Singapore National University of Singapore Singapore Singapore
                Author notes
                [*] [* ] Correspondence

                Zhaowu Ma and Jiang‐Rong Huang, Health Science Center, Yangtze University, Nanhuan Road 1, Jingzhou, Hubei 434023, China.

                Email: mazw@ 123456yangtzeu.edu.cn ; huangjr999@ 123456sina.com

                Gautam Sethi, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.

                Email: phcgs@ 123456nus.edu.sg

                Author information
                https://orcid.org/0000-0001-7923-1677
                https://orcid.org/0000-0002-4720-9659
                https://orcid.org/0000-0003-2841-7273
                https://orcid.org/0000-0001-5585-5426
                https://orcid.org/0000-0001-9033-4765
                https://orcid.org/0000-0002-8677-8475
                https://orcid.org/0000-0001-7675-1845
                Article
                CPR13143
                10.1111/cpr.13143
                8666285
                34672397
                3a5026ae-fe56-41e6-8084-3d90605ba946
                © 2021 The Authors. Cell Proliferation published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 September 2021
                : 14 August 2021
                : 03 October 2021
                Page count
                Figures: 5, Tables: 1, Pages: 0, Words: 9644
                Funding
                Funded by: Natural Science Foundation of Hubei Province
                Award ID: 2019CFB591
                Funded by: Bureau of Science and Technology of Jingzhou Municipality
                Award ID: 2020CB21‐35
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                December 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.9 mode:remove_FC converted:12.12.2021

                Cell biology
                Cell biology

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