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• W3157665749 abstract "Some circRNAs have been shown to encode peptides, which may reiterate the concept that some of these circular transcripts should be redefined as coding transcripts.We propose the protein bait hypothesis to describe the functional mechanisms of circRNA-encoded proteins.circRNA-encoded proteins have distinctive characteristics, such as high sequence homology with mRNA-encoded isoforms and short length, enabling them to function as baits that competitively bind to partners of cognate proteins.The protein bait hypothesis can be used to explain various biological phenomena, and design therapeutic interventions for different pathophysiological events. Recent studies have demonstrated that a large group of proteins encoded by circular RNAs (circRNAs) are likely to play a role in cancer development; however, there remains a substantial gap in our understanding of this group of proteins and their functional mechanisms involved. Therefore, we propose the protein bait hypothesis, which specifies that circRNA-encoded proteins compete with their cognate linearly spliced protein isoforms for binding molecules, preventing proper isoform functioning. This hypothesis may expand our understanding of the functional mechanisms of circRNA-encoded proteins and prove useful in elucidating the mechanisms underlying human development, physiology, and diseases, and in parallel, also aid in drug discovery. Recent studies have demonstrated that a large group of proteins encoded by circular RNAs (circRNAs) are likely to play a role in cancer development; however, there remains a substantial gap in our understanding of this group of proteins and their functional mechanisms involved. Therefore, we propose the protein bait hypothesis, which specifies that circRNA-encoded proteins compete with their cognate linearly spliced protein isoforms for binding molecules, preventing proper isoform functioning. This hypothesis may expand our understanding of the functional mechanisms of circRNA-encoded proteins and prove useful in elucidating the mechanisms underlying human development, physiology, and diseases, and in parallel, also aid in drug discovery. circRNAs have recently emerged as a significant class of endogenous noncoding RNAs with covalently closed structures generated by back splicing. These circular transcripts participate in a variety of biological processes through diverse mechanisms [1.Kristensen L.S. et al.Circular RNAs in cancer: opportunities and challenges in the field.Oncogene. 2018; 37: 555-565Crossref PubMed Scopus (678) Google Scholar,2.Kristensen L.S. et al.The biogenesis, biology and characterization of circular RNAs.Nat. Rev. Genet. 2019; 20: 675-691Crossref PubMed Scopus (915) Google Scholar], such as the post-transcriptional regulation of mRNAs as miRNA sponges [3.Salmena L. et al.A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language?.Cell. 2011; 146: 353-358Abstract Full Text Full Text PDF PubMed Scopus (3789) Google Scholar]. Intriguingly, some circRNAs have been shown to encode peptides whose functions are yet unknown [4.van Heesch S. et al.The translational landscape of the human heart.Cell. 2019; 178: 242-260 e29Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar,5.Chen X. et al.circRNADb: a comprehensive database for human circular RNAs with protein-coding annotations.Sci. Rep. 2016; 6: 34985Crossref PubMed Scopus (221) Google Scholar]. This may reiterate the concept that some circRNAs should be redefined as coding transcripts [6.Lei M. et al.Translation and functional roles of circular RNAs in human cancer.Mol. Cancer. 2020; 19: 30Crossref PubMed Scopus (109) Google Scholar,7.Wu P. et al.Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA.Mol. Cancer. 2020; 19: 22Crossref PubMed Scopus (109) Google Scholar]. Some circRNAs, particularly those of the exonic type, have been shown to contain putative open reading frames (ORFs) that can actively undergo translation, sometimes through overlapping codons due to the unique loop structure [8.Zhang M. et al.A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis.Oncogene. 2018; 37: 1805-1814Crossref PubMed Scopus (292) Google Scholar]. Unlike mRNAs, circRNAs are translated via cap-independent mechanisms that rely on the internal ribosome entry site (IRES) [9.Chen C.Y. Sarnow P. Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs.Science. 1995; 268: 415-417Crossref PubMed Scopus (433) Google Scholar] and N6-methyladenosine (m6A) modification of RNA [10.Yang Y. et al.Extensive translation of circular RNAs driven by N(6)-methyladenosine.Cell Res. 2017; 27: 626-641Crossref PubMed Scopus (751) Google Scholar] (Box 1). Recent studies have demonstrated that a large group of proteins encoded by circRNAs may be associated with various physiological and pathological processes, such as tumorigenesis [4.van Heesch S. et al.The translational landscape of the human heart.Cell. 2019; 178: 242-260 e29Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 5.Chen X. et al.circRNADb: a comprehensive database for human circular RNAs with protein-coding annotations.Sci. Rep. 2016; 6: 34985Crossref PubMed Scopus (221) Google Scholar, 6.Lei M. et al.Translation and functional roles of circular RNAs in human cancer.Mol. Cancer. 2020; 19: 30Crossref PubMed Scopus (109) Google Scholar,11.Legnini I. et al.Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis.Mol. Cell. 2017; 66: 22-37 e9Abstract Full Text Full Text PDF PubMed Scopus (995) Google Scholar]. Nevertheless, there remains a substantial gap in our understanding of these newly identified proteins and their mechanisms of function.Box 1Cap-Independent Translation Initiation Mechanisms of the circRNAscircRNAs can only be translated in a cap-independent manner due to the lack of a 5′ cap. IRES- and N6-methyladenosine (m6A)-mediated translation initiation are two widely accepted processes of circRNA translation [7.Wu P. et al.Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA.Mol. Cancer. 2020; 19: 22Crossref PubMed Scopus (109) Google Scholar]. IRES elements were initially identified in viral RNAs, and are described as RNA regulatory elements that recruit ribosomes, allowing for the initiation of cap-independent translation [41.Yang Y. Wang Z. IRES-mediated cap-independent translation, a path leading to hidden proteome.J. Mol. Cell Biol. 2019; 11: 911-919Crossref PubMed Scopus (38) Google Scholar]. Typically, this IRES-driven manner involves IRES-transacting factors that can recruit ribosomes to the internal structure of the RNAs. It has been shown that eukaryotic mRNAs can initially be translated through the IRES-mediated process under physiological and environmental stress [42.Godet A.C. et al.IRES trans-acting factors, key actors of the stress response.Int. J. Mol. Sci. 2019; 20Crossref PubMed Scopus (37) Google Scholar]. This is as an alternative translation mechanism in eukaryotes that compensates for defective cap-dependent translation. Studies have confirmed that this model can also be applied to circRNAs. For example, circ-ZNF609 could code for peptides in a cap-independent manner, and was initiated by IRES elements in untranslated regions [11.Legnini I. et al.Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis.Mol. Cell. 2017; 66: 22-37 e9Abstract Full Text Full Text PDF PubMed Scopus (995) Google Scholar]. IRES-mediated translation may be prevalent in circRNA translation, since any circRNAs with a fragment longer than 50 nt can theoretically contain an IRES-like hexamer [6.Lei M. et al.Translation and functional roles of circular RNAs in human cancer.Mol. Cancer. 2020; 19: 30Crossref PubMed Scopus (109) Google Scholar].Another important cap-independent translation mechanism is through a short sequence containing the m6A site. The m6A is an abundant modification in mRNA and DNA in higher-order organisms [43.Roundtree I.A. et al.Dynamic RNA modifications in gene expression regulation.Cell. 2017; 169: 1187-1200Abstract Full Text Full Text PDF PubMed Scopus (958) Google Scholar]. This modification is also found in non-coding RNAs, such as long noncoding RNAs and circRNAs, and influences the regulations of gene expression, RNA stability, localization, and translation [44.Meyer K.D. Jaffrey S.R. The dynamic epitranscriptome: N6-methyladenosine and gene expression control.Nat. Rev. Mol. Cell Biol. 2014; 15: 313-326Crossref PubMed Scopus (481) Google Scholar]. Yang et al. found that a single m6A site is sufficient to initiate circRNA translation, which also requires initiation factor eIF4G2 and the m6A reader, YTHDF3 [10.Yang Y. et al.Extensive translation of circular RNAs driven by N(6)-methyladenosine.Cell Res. 2017; 27: 626-641Crossref PubMed Scopus (751) Google Scholar]. Moreover, this mode of translation is enhanced by the methyltransferase METTL3/14, suppressed by the demethylase FTO, and is activated especially under heat shock conditions [10.Yang Y. et al.Extensive translation of circular RNAs driven by N(6)-methyladenosine.Cell Res. 2017; 27: 626-641Crossref PubMed Scopus (751) Google Scholar].Although IRES and m6A have been shown to be important translation initiation drivers, the translation mechanism that many coding circRNAs undergo is still unknown. Future studies could focus on identifying the preferred translation mechanism of circRNAs and investigate the relationship between this preference and the translation product-mediated biological process. circRNAs can only be translated in a cap-independent manner due to the lack of a 5′ cap. IRES- and N6-methyladenosine (m6A)-mediated translation initiation are two widely accepted processes of circRNA translation [7.Wu P. et al.Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA.Mol. Cancer. 2020; 19: 22Crossref PubMed Scopus (109) Google Scholar]. IRES elements were initially identified in viral RNAs, and are described as RNA regulatory elements that recruit ribosomes, allowing for the initiation of cap-independent translation [41.Yang Y. Wang Z. IRES-mediated cap-independent translation, a path leading to hidden proteome.J. Mol. Cell Biol. 2019; 11: 911-919Crossref PubMed Scopus (38) Google Scholar]. Typically, this IRES-driven manner involves IRES-transacting factors that can recruit ribosomes to the internal structure of the RNAs. It has been shown that eukaryotic mRNAs can initially be translated through the IRES-mediated process under physiological and environmental stress [42.Godet A.C. et al.IRES trans-acting factors, key actors of the stress response.Int. J. Mol. Sci. 2019; 20Crossref PubMed Scopus (37) Google Scholar]. This is as an alternative translation mechanism in eukaryotes that compensates for defective cap-dependent translation. Studies have confirmed that this model can also be applied to circRNAs. For example, circ-ZNF609 could code for peptides in a cap-independent manner, and was initiated by IRES elements in untranslated regions [11.Legnini I. et al.Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis.Mol. Cell. 2017; 66: 22-37 e9Abstract Full Text Full Text PDF PubMed Scopus (995) Google Scholar]. IRES-mediated translation may be prevalent in circRNA translation, since any circRNAs with a fragment longer than 50 nt can theoretically contain an IRES-like hexamer [6.Lei M. et al.Translation and functional roles of circular RNAs in human cancer.Mol. Cancer. 2020; 19: 30Crossref PubMed Scopus (109) Google Scholar]. Another important cap-independent translation mechanism is through a short sequence containing the m6A site. The m6A is an abundant modification in mRNA and DNA in higher-order organisms [43.Roundtree I.A. et al.Dynamic RNA modifications in gene expression regulation.Cell. 2017; 169: 1187-1200Abstract Full Text Full Text PDF PubMed Scopus (958) Google Scholar]. This modification is also found in non-coding RNAs, such as long noncoding RNAs and circRNAs, and influences the regulations of gene expression, RNA stability, localization, and translation [44.Meyer K.D. Jaffrey S.R. The dynamic epitranscriptome: N6-methyladenosine and gene expression control.Nat. Rev. Mol. Cell Biol. 2014; 15: 313-326Crossref PubMed Scopus (481) Google Scholar]. Yang et al. found that a single m6A site is sufficient to initiate circRNA translation, which also requires initiation factor eIF4G2 and the m6A reader, YTHDF3 [10.Yang Y. et al.Extensive translation of circular RNAs driven by N(6)-methyladenosine.Cell Res. 2017; 27: 626-641Crossref PubMed Scopus (751) Google Scholar]. Moreover, this mode of translation is enhanced by the methyltransferase METTL3/14, suppressed by the demethylase FTO, and is activated especially under heat shock conditions [10.Yang Y. et al.Extensive translation of circular RNAs driven by N(6)-methyladenosine.Cell Res. 2017; 27: 626-641Crossref PubMed Scopus (751) Google Scholar]. Although IRES and m6A have been shown to be important translation initiation drivers, the translation mechanism that many coding circRNAs undergo is still unknown. Future studies could focus on identifying the preferred translation mechanism of circRNAs and investigate the relationship between this preference and the translation product-mediated biological process. While the genetic sources of coding circRNAs are complex, it is possible that circRNA-encoded proteins, even with considerable structural heterogeneity, follow similar functional mechanisms. This Opinion proposes that homogeneity between circRNA-encoded proteins and their cognate linearly spliced protein isoforms is a point of convergence across the molecular mechanisms of these newly discovered proteins. These ideas have originated from recent research, which shows that circRNA-encoded proteins that competitively bind with their associated factors affect the posttranslational modification of the cognate isoforms dependent on the homologous sequence. Firstly, we outline the theoretical model and then propose its prerequisites. Secondly, we provide several lines of supporting evidence and finally suggest how this model might be used as an explanation of biological phenomena, and therapeutic interventions across different pathophysiological events. Approximately 20 000 protein-coding genes of the human genome have been annotated and identified so far [12.Consortium, E.P An integrated encyclopedia of DNA elements in the human genome.Nature. 2012; 489: 57-74Crossref PubMed Scopus (9795) Google Scholar, 13.Kim M.S. et al.A draft map of the human proteome.Nature. 2014; 509: 575-581Crossref PubMed Scopus (1349) Google Scholar, 14.Wilhelm M. et al.Mass-spectrometry-based draft of the human proteome.Nature. 2014; 509: 582-587Crossref PubMed Scopus (1193) Google Scholar]. Given that a single gene can yield multiple mRNAs through the alternative splicing of exons [15.Liu Y. et al.Impact of alternative splicing on the human proteome.Cell Rep. 2017; 20: 1229-1241Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar], a staggering half-million functionally distinct proteins can be encoded by the human genome [16.Nilsen T.W. Graveley B.R. Expansion of the eukaryotic proteome by alternative splicing.Nature. 2010; 463: 457-463Crossref PubMed Scopus (1250) Google Scholar,17.Berggard T. et al.Methods for the detection and analysis of protein-protein interactions.Proteomics. 2007; 7: 2833-2842Crossref PubMed Scopus (368) Google Scholar]. Proteins control nearly all biological processes, and the structure and function of tissues and organs, while functional abnormalities in proteins form the basis of numerous diseases. Thus, delineating factors that govern protein activity in cells is a fundamental research topic in biology [18.Wang D. et al.A deep proteome and transcriptome abundance atlas of 29 healthy human tissues.Mol. Syst. Biol. 2019; 15e8503Crossref PubMed Scopus (166) Google Scholar]. The biological properties of proteins are based on their ability to recognize and bind to the interacting partners, such as lipids, proteins, DNA, RNA, ions, and metabolites, and to undergo necessary conformational changes [19.Alberts B. et al.Molecular Biology of the Cell.6th edn. Garland Science, 2014Crossref Google Scholar]. For a better understanding of the protein bait hypothesis, we have defined the binding partners in this context as helpers or effectors, depending on the roles played in biological processes. Helpers include ligands in ligand–receptor interactions and enzymes catalyzing post-translational modifications that confer functional properties to the proteins. Effectors consist of receptors and substrates in the aforementioned scenarios that directly trigger downstream signal transduction pathways. One of the most striking characteristic biological properties of proteins, that is, their interaction with binding partners raises the following question: what are the factors that serve as ‘brakes’ for the theoretically abstemious interactions in eukaryotes? We surmise that certain distinctive characteristics of circRNA-encoded proteins enable them to function as baits that competitively bind to the partners of cognate functional proteins, thereby indirectly putting brakes on the latter’s function (Figure 1A–C ). The molecular characteristics of circRNA-encoded proteins provide strong support for this hypothesis. For further analysis, we selected eight proteins with known functions and 40 other proteins identified by Heesch et al. through ribosomal profiling [4.van Heesch S. et al.The translational landscape of the human heart.Cell. 2019; 178: 242-260 e29Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar,8.Zhang M. et al.A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis.Oncogene. 2018; 37: 1805-1814Crossref PubMed Scopus (292) Google Scholar,11.Legnini I. et al.Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis.Mol. Cell. 2017; 66: 22-37 e9Abstract Full Text Full Text PDF PubMed Scopus (995) Google Scholar,20.Zheng X. et al.A novel protein encoded by a circular RNA circPPP1R12A promotes tumor pathogenesis and metastasis of colon cancer via Hippo-YAP signaling.Mol. Cancer. 2019; 18: 47Crossref PubMed Scopus (152) Google Scholar, 21.Xia X. et al.A novel tumor suppressor protein encoded by circular AKT3 RNA inhibits glioblastoma tumorigenicity by competing with active phosphoinositide-dependent Kinase-1.Mol. Cancer. 2019; 18: 131Crossref PubMed Scopus (89) Google Scholar, 22.Zhi X. et al.circLgr4 drives colorectal tumorigenesis and invasion through Lgr4-targeting peptide.Int. J. Cancer. 2019; (Published online July 3, 2019. https://doi.org/10.1002/ijc.32549)Crossref Google Scholar, 23.Yang Y. et al.Novel role of FBXW7 circular RNA in repressing glioma tumorigenesis.J. Natl. Cancer Inst. 2018; 110Crossref PubMed Scopus (505) Google Scholar, 24.Liang W.C. et al.Translation of the circular RNA circbeta-catenin promotes liver cancer cell growth through activation of the Wnt pathway.Genome Biol. 2019; 20: 84Crossref PubMed Scopus (165) Google Scholar] (Box 2). We found that nearly all protein-coding circRNAs are transcribed from the canonical protein-coding regions of the genes (Figure 2A ). Thus, it is not surprising that proteins encoded by circRNAs and their cognate mRNAs show a considerable degree of sequence homology (Figure 2B), suggesting similarity in their spatial conformations. We analyzed the structural homologs of circRNA-encoded proteins and their corresponding cognate isoforms using the SARST method [25.Lo W.C. et al.Protein structural similarity search by Ramachandran codes.BMC Bioinformatics. 2007; 8: 307Crossref PubMed Scopus (43) Google Scholar], and observed that they usually share highly conserved 3D structures, as exemplified by the proteins encoded by circNUDC and circβ-catenin and their cognate mRNA-encoded proteins (Figure 2C). This result demonstrated that the circRNA-specific sequence-mediated effect was limited to the 3D structure created by the conserved sequence.Box 2How circRNA-Encoded Proteins Are IdentifiedThe determination of a circRNA as a coding transcript requires the evaluation of coding potential using bioinformatics tools and objective evidence provided by experimental approaches.Predicting circRNA coding potential includes the assessment of the ORF and the translation initiation component of the circRNA sequence. An ORF could be translated, which continues in three-base sets that starting with a start codon (usually AUG) and ending at a stop codon (usually UAA, UAG, or UGA). The presence of an ORF in circRNA, usually spanning the splicing site, is a prerequisite for translation. Several algorithms have been proposed to predict ORF, such as the widely used ORF Finder and Coding-Potential Calculator (CPC) [6.Lei M. et al.Translation and functional roles of circular RNAs in human cancer.Mol. Cancer. 2020; 19: 30Crossref PubMed Scopus (109) Google Scholar,45.Kong L. et al.CPC: assess the protein-coding potential of transcripts using sequence features and support vector machine.Nucleic Acids Res. 2007; 35: W345-W349Crossref PubMed Scopus (1506) Google Scholar]. ORF translation is driven by translation initiation components, highlighting the importance in predicting these components for the evaluation of coding potential. Based on the current understanding of circRNA translation in eukaryotic cells, IRES- or m6A-modified conserved sites upstream of ORF mediate circRNA translation [7.Wu P. et al.Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA.Mol. Cancer. 2020; 19: 22Crossref PubMed Scopus (109) Google Scholar]. Databases that can be used to predict the initiation components, such as IRESite [46.Mokrejs M. et al.IRESite – a tool for the examination of viral and cellular internal ribosome entry sites.Nucleic Acids Res. 2010; 38: D131-D136Crossref PubMed Scopus (103) Google Scholar] and IRESfinder [47.Zhao J. et al.IRESfinder: Identifying RNA internal ribosome entry site in eukaryotic cell using framed k-mer features.J. Genet Genomics. 2018; 45: 403-406Crossref PubMed Scopus (23) Google Scholar] for IRES, and DeepM6ASeq [48.Zhang Y. Hamada M. DeepM6ASeq: prediction and characterization of m6A-containing sequences using deep learning.BMC Bioinformatics. 2018; 19: 524Crossref PubMed Scopus (40) Google Scholar] and M6APred-EL [49.Wei L. et al.M6APred-EL: a sequence-based predictor for identifying N6-methyladenosine sites using ensemble learning.Mol. Ther. Nucleic Acids. 2018; 12: 635-644Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar] for m6A, have been developed. Recently, integrated bioinformatics tools, allowing identification of both the ORF and the initiation components, such as CircBank [50.Liu M. et al.Circbank: a comprehensive database for circRNA with standard nomenclature.RNA Biol. 2019; 16: 899-905Crossref PubMed Scopus (79) Google Scholar], have also been established. Notably, according to the coding potential assessment in CircBank, 45.6% of circRNAs have a coding probability of >90%, and 41.4% have a coding probability of >95%.The final determination of circRNA translation requires objective evidence provided by various experimental approaches. Translational omics analyses, including polysome profiling, ribosome immunoprecipitation/ribosome affinity purification, ribosome profiling, and ribosome-nascent chain complex sequencing, are high-throughput techniques that allow for the identification of circRNAs being translated [7.Wu P. et al.Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA.Mol. Cancer. 2020; 19: 22Crossref PubMed Scopus (109) Google Scholar]. Proteomics analyses, such as liquid chromatography tandem mass spectrometry, can directly identify peptides, which provide the most intuitive evidence of circRNA translation. Molecular cloning techniques have also been used for the identification of circRNA translation. For the verification of a translatable ORF, FLAG-labeled vectors are used to express linear or circular forms of the circRNA ORF, which then allows for western blotting analysis to be used to identify the targeted protein using a FLAG antibody. Alternatively, a specific antibody against the unique sequence of circRNA-encoded protein can be used to directly detect putative peptides. To demonstrate the translation-initiation ability of IRES, dual luciferase reporting assays can be used to test the wild-type and mutated circRNA IRES activity. The determination of a circRNA as a coding transcript requires the evaluation of coding potential using bioinformatics tools and objective evidence provided by experimental approaches. Predicting circRNA coding potential includes the assessment of the ORF and the translation initiation component of the circRNA sequence. An ORF could be translated, which continues in three-base sets that starting with a start codon (usually AUG) and ending at a stop codon (usually UAA, UAG, or UGA). The presence of an ORF in circRNA, usually spanning the splicing site, is a prerequisite for translation. Several algorithms have been proposed to predict ORF, such as the widely used ORF Finder and Coding-Potential Calculator (CPC) [6.Lei M. et al.Translation and functional roles of circular RNAs in human cancer.Mol. Cancer. 2020; 19: 30Crossref PubMed Scopus (109) Google Scholar,45.Kong L. et al.CPC: assess the protein-coding potential of transcripts using sequence features and support vector machine.Nucleic Acids Res. 2007; 35: W345-W349Crossref PubMed Scopus (1506) Google Scholar]. ORF translation is driven by translation initiation components, highlighting the importance in predicting these components for the evaluation of coding potential. Based on the current understanding of circRNA translation in eukaryotic cells, IRES- or m6A-modified conserved sites upstream of ORF mediate circRNA translation [7.Wu P. et al.Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA.Mol. Cancer. 2020; 19: 22Crossref PubMed Scopus (109) Google Scholar]. Databases that can be used to predict the initiation components, such as IRESite [46.Mokrejs M. et al.IRESite – a tool for the examination of viral and cellular internal ribosome entry sites.Nucleic Acids Res. 2010; 38: D131-D136Crossref PubMed Scopus (103) Google Scholar] and IRESfinder [47.Zhao J. et al.IRESfinder: Identifying RNA internal ribosome entry site in eukaryotic cell using framed k-mer features.J. Genet Genomics. 2018; 45: 403-406Crossref PubMed Scopus (23) Google Scholar] for IRES, and DeepM6ASeq [48.Zhang Y. Hamada M. DeepM6ASeq: prediction and characterization of m6A-containing sequences using deep learning.BMC Bioinformatics. 2018; 19: 524Crossref PubMed Scopus (40) Google Scholar] and M6APred-EL [49.Wei L. et al.M6APred-EL: a sequence-based predictor for identifying N6-methyladenosine sites using ensemble learning.Mol. Ther. Nucleic Acids. 2018; 12: 635-644Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar] for m6A, have been developed. Recently, integrated bioinformatics tools, allowing identification of both the ORF and the initiation components, such as CircBank [50.Liu M. et al.Circbank: a comprehensive database for circRNA with standard nomenclature.RNA Biol. 2019; 16: 899-905Crossref PubMed Scopus (79) Google Scholar], have also been established. Notably, according to the coding potential assessment in CircBank, 45.6% of circRNAs have a coding probability of >90%, and 41.4% have a coding probability of >95%. The final determination of circRNA translation requires objective evidence provided by various experimental approaches. Translational omics analyses, including polysome profiling, ribosome immunoprecipitation/ribosome affinity purification, ribosome profiling, and ribosome-nascent chain complex sequencing, are high-throughput techniques that allow for the identification of circRNAs being translated [7.Wu P. et al.Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA.Mol. Cancer. 2020; 19: 22Crossref PubMed Scopus (109) Google Scholar]. Proteomics analyses, such as liquid chromatography tandem mass spectrometry, can directly identify peptides, which provide the most intuitive evidence of circRNA translation. Molecular cloning techniques have also been used for the identification of circRNA translation. For the verification of a translatable ORF, FLAG-labeled vectors are used to express linear or circular forms of the circRNA ORF, which then allows for western blotting analysis to be used to identify the targeted protein using a FLAG antibody. Alternatively, a specific antibody against the unique sequence of circRNA-encoded protein can be used to directly detect putative peptides. To demonstrate the translation-initiation ability of IRES, dual luciferase reporting assays can be used to test the wild-type and mutated circRNA IRES activity. Furthermore, we compared the lengths of mRNA-encoded proteins from the Universal Protein Resource (UniProt) with circRNA-encoded proteins and found that the latter are often shorter (Figure 2D). This difference in lengths suggests that proteins translated from circRNAs tend to expose their binding sites due to a lack of surface shielding domains, and their activity differs from that of the cognate functional proteins. Additionally, >200 000 circRNAs have been identified in human tissues to date [26.Vo J.N. et al.The landscape of circular RNA in cancer.Cell. 2019; 176: 869-881 e13Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar,27.Ji P. et al.Expanded expression landscape and prioritization of circular RNAs in mammals.Cell Rep. 2019; 26: 3444-3460 e5Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar]. Thi" @default.
• W3157665749 created "2021-05-10" @default.
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• W3157665749 date "2021-07-01" @default.
• W3157665749 modified "2023-09-28" @default.
• W3157665749 title "Protein Bait Hypothesis: circRNA-Encoded Proteins Competitively Inhibit Cognate Functional Isoforms" @default.
• W3157665749 cites W1986469266 @default.
• W3157665749 cites W1986988560 @default.
• W3157665749 cites W2023036977 @default.
• W3157665749 cites W2046387002 @default.
• W3157665749 cites W2056499061 @default.
• W3157665749 cites W2063530272 @default.
• W3157665749 cites W2069860553 @default.
• W3157665749 cites W2075320162 @default.
• W3157665749 cites W2076443836 @default.
• W3157665749 cites W2094813328 @default.
• W3157665749 cites W2095748631 @default.
• W3157665749 cites W2105632053 @default.
• W3157665749 cites W2128900650 @default.
• W3157665749 cites W2140537006 @default.
• W3157665749 cites W2259938310 @default.
• W3157665749 cites W2530008209 @default.
• W3157665749 cites W2574203317 @default.
• W3157665749 cites W2592988313 @default.
• W3157665749 cites W2601436215 @default.
• W3157665749 cites W2612976808 @default.
• W3157665749 cites W2621361823 @default.
• W3157665749 cites W2627064270 @default.
• W3157665749 cites W2741879909 @default.
• W3157665749 cites W2750771238 @default.
• W3157665749 cites W2752880228 @default.
• W3157665749 cites W2764294957 @default.
• W3157665749 cites W2783029521 @default.
• W3157665749 cites W2813360597 @default.
• W3157665749 cites W2884961061 @default.
• W3157665749 cites W2897137698 @default.
• W3157665749 cites W2906996182 @default.
• W3157665749 cites W2909535269 @default.
• W3157665749 cites W2912017471 @default.
• W3157665749 cites W2925033480 @default.
• W3157665749 cites W2935104625 @default.
• W3157665749 cites W2942409680 @default.
• W3157665749 cites W2944031662 @default.
• W3157665749 cites W2944606734 @default.
• W3157665749 cites W2947880448 @default.
• W3157665749 cites W2950512597 @default.
• W3157665749 cites W2956069913 @default.
• W3157665749 cites W2967043226 @default.
• W3157665749 cites W2971055195 @default.
• W3157665749 cites W2971386099 @default.
• W3157665749 cites W2989389674 @default.
• W3157665749 cites W3006194842 @default.
• W3157665749 cites W3006786463 @default.
• W3157665749 cites W3020855961 @default.
• W3157665749 cites W4251118184 @default.
• W3157665749 doi "https://doi.org/10.1016/j.tig.2021.04.002" @default.
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