Skip to main content

Advertisement

SpringerLink
Log in

The new function of circRNA: translation

  • Review Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Circular RNAs (circRNAs) have been considered a special class of non-coding RNAs without 5′ caps and 3′ tails which are covalently closed RNA molecules generated by back splicing of mRNA. For a long time, circRNAs have been considered to be directly involved in various biological processes as functional RNA. In recent years, a variety of circRNAs have been found to have translational functions, and the resultant peptides also play biological roles in the emergence and progression of human disease. The discovery of these circRNAs and their encoded peptides has enriched genomics, helped us to study the causes of diseases, and promoted the development of biotechnology. The purpose of this review is to summarize the research progress of the detection methods, translation initiation mechanism, as well as functional mechanism of peptides encoded by circRNAs, with the goal of providing the directions for the discovery of biomarkers for diagnosis, prognosis, and therapeutic targets for human disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

circRNA:

Circular RNA

IRES:

Internal ribosome entry site

ORF:

Open reading frame

eIF:

Eukaryotic initiation factor

m6A:

N6-methyladenosine

YTHDF1/2/3:

YTH domain family protein 1/2/3

GFP:

Green fluorescent protein

Rluc:

Rellina luciferase

Luc:

Luciferase

PCNA:

Proliferating cell nuclear antigen

USP28:

Ubiquitin-specific protease 28

GSK3β:

Glycogen synthase kinase 3 beta

AKT3:

Protein kinase B γ

PDK1:

Pyruvate dehydrogenase kinase isozyme 1

YAP1:

Yes-associated protein 1

PAF1:

Polymerase-associated factor

GPCR:

G-protein-coupled receptor

Rspo:

R-spondins

METTL3/14:

Methyltransferase-like 3/14

FTO:

Fat mass and obesity-associated protein

ALKBH5:

ALKB homolog 5

IME:

Intron-mediated enhancement

References

  1. Pamudurti NR, Bartok O, Jens M, et al. Translation of CircRNAs. Mol Cell. 2017;66:9–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Chekulaeva M Rajewsky N. Roles of long noncoding RNAs and circular RNAs in Translation. Cold Spring Harb Perspect Biol. 2019;11:a032680.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Sanger HL, Klotz G, Riesner D, et al. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc Natl Acad Sci USA. 1976;73:3852–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Jeck WR, Sorrentino JA, Wang K, et al. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA. 2013;19:141–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Vo JN, Cieslik M, Zhang Y, et al. The landscape of circular RNA in cancer. Cell. 2019;176:869–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang Y, Zhang XO, Chen T, et al. Circular intronic long noncoding RNAs. Mol Cell. 2013;51:792–806.

    CAS  PubMed  Google Scholar 

  7. Zganiacz D, Milanowski R. Characteristics of circular ribonucleic acid molecules (circRNA). Postepy Biochem. 2017;63:221–32.

    PubMed  Google Scholar 

  8. Chen N, Zhao G, Yan X, et al. A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1. Genome Biol. 2018;19:218.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Li Z, Huang C, Bao C, et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 2015;22:256–64.

    PubMed  Google Scholar 

  10. Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495:333–8.

    CAS  PubMed  Google Scholar 

  11. Conn VM, Hugouvieux V, Nayak A, et al. A circRNA from SEPALLATA3 regulates splicing of its cognate mRNA through R-loop formation. Nat Plants. 2017;3:17053.

    CAS  PubMed  Google Scholar 

  12. Fu L, Chen Q, Yao T, et al. Hsa_circ_0005986 inhibits carcinogenesis by acting as a miR-129-5p sponge and is used as a novel biomarker for hepatocellular carcinoma. Oncotarget. 2017;8:43878–88.

    PubMed  PubMed Central  Google Scholar 

  13. Chen L, Zhang S, Wu J, et al. CircRNA_100290 plays a role in oral cancer by functioning as a sponge of the miR-29 family. Oncogene. 2017;36:4551–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Han D, Li J, Wang H, et al. Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression. Hepatology. 2017;66:1151–64.

    CAS  PubMed  Google Scholar 

  15. Du WW, Yang W, Liu E, et al. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res. 2016;44:2846–58.

    PubMed  PubMed Central  Google Scholar 

  16. Du WW, Fang L, Yang W, et al. Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity. Cell Death Differ. 2017;24:357–70.

    CAS  PubMed  Google Scholar 

  17. Bi W, Huang J, Nie C, et al. CircRNA circRNA_102171 promotes papillary thyroid cancer progression through modulating CTNNBIP1-dependent activation of β-catenin pathway. J Exp Clin Cancer Res. 2018;37:275.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Chang CY, Sarnow P. Initiation of protein synthesis by the eukaryotic. Transl Appar Circ RNAs Sci. 1995;268:415–7.

    Google Scholar 

  19. Xia X, Li X, Li F, 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;18:131.

    PubMed  PubMed Central  Google Scholar 

  20. Zheng X, Chen L, Zhou Y, 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;18:47.

    PubMed  PubMed Central  Google Scholar 

  21. Zhang M, Huang N, Yang X, et al. A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis. Oncogene. 2019;37:1805–14.

    Google Scholar 

  22. Yang Y, Gao X, Zhang M, et al. Novel role of FBXW7 circular RNA in Repressing glioma tumorigenesis. J Natl Cancer Inst. 2018;110:304–15.

    CAS  Google Scholar 

  23. Zhang M, Zhao K, Xu X, et al. A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. Nat Commun. 2018;9:4475.

    PubMed  PubMed Central  Google Scholar 

  24. Legnini L, Di Timoteo G, Rossi F, et al. Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis. Mol Cell. 2017;66:22–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhao J, Lee EE, Kim J, et al. Transforming activity of an oncoprotein-encoding circular RNA from human papillomavirus. Nat Commun. 2019;10:2300.

    PubMed  PubMed Central  Google Scholar 

  26. Liang WC, Wong CW, Liang PP, et al. Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway. Genome Biol. 2019;20:84.

    PubMed  PubMed Central  Google Scholar 

  27. Banko JL, Klann E. Cap-dependent translation initiation and memory. Prog Brain Res. 2008;169:59–80.

    CAS  PubMed  Google Scholar 

  28. Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell. 2009;136:731–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Merrick WC. Cap-dependent and cap-independent translation in eukaryotic systems. Gene. 2004;332:1–11.

    CAS  PubMed  Google Scholar 

  30. Yang Y, Fan X, Mao M, et al. Extensive translation of circular RNAs driven by N6-methyladenosine. Cell Res. 2017;27:626–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Gu C, Zhou N, Wang Z, et al. CircGprc5a promoted bladder oncogenesis and metastasis through Gprc5a-targeting peptide. Mol Ther Nucleic Acids. 2018;13:633–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhi X, Zhang J, Cheng Z, et al. CircLgr4 drives colorectal tumorigenesis and invasion through Lgr4-targeting peptide. Int J Cancer. 2019. https://doi.org/10.1002/ijc.32549.

    Article  PubMed  Google Scholar 

  33. Imataka H, Olsen HS, Sonenberg N. A new translational regulator with homology to eukaryotic translation initiation factor 4G. EMBO J. 1997;16:817–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Morino S, Imataka H, Svitkin YV, et al. Eukaryotic translation initiation factor 4E (eIF4E) binding site and the middle one-third of eIF4GI constitute the core domain for cap- dependent translation, and the C-terminal one-third functions as a modulatory region. Mol Cell Biol. 2000;20:468–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Liberman N, Gandin V, Svitkin YV, et al. DAP5 associates with eIF2β and eIF4AI to promote internal ribosome entry site driven translation. Nucleic Acids Res. 2015;43:3764–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Lamphear BJ, Kirchweger R, Skern T, et al. Mapping of functional domains in eukaryotic protein synthesis initiation factor 4G (eIF4G) with picornaviral proteases. Implications for cap-dependent and cap-independent translational initiation. J Biol Chem. 1995;270:21975–83.

    CAS  PubMed  Google Scholar 

  37. Hellen CU, Sarnow P. Internal ribosome entry sites in eukaryotic mRNA molecules. Genes Dev. 2001;15:1593–612.

    CAS  PubMed  Google Scholar 

  38. Kearse MG, Wilusz JE. Non-AUG translation: a new start for protein synthesis in eukaryotes. Genes Dev. 2017;31:1717–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Abe N, Hiroshima M, Maruyama H, et al. Rolling circle amplification in a prokaryotic translation system using small circular RNA. Angew Chem Int Ed Engl. 2013;52:7004–8.

    CAS  PubMed  Google Scholar 

  40. Abe N, Matsumoto K, Nishihara M, et al. Rolling circle translation of circular RNA in living human cells. Sci Rep. 2015;5:16435.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Warner JR, Knopf PM, Rich A. A multiple ribosomal structure in protein synthesis. Proc Natl Acad Sci USA. 1963;49:122–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Chassé H, Boulben S, Costache V, et al. Analysis of translation using polysome profiling. Nucleic Acids Res. 2017;45:e15.

    PubMed  Google Scholar 

  43. Ingolia NT, Ghaemmaghami S, Newman JR, et al. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science. 2009;324:218–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Ingolia NT, Brar GA, Rouskin S, et al. The ribosome profiling strategy for monitoring translation in vivo by deep sequencing of ribosome-protected mRNA fragments. Nat Protoc. 2012;7:1534–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Dudekula DB, Panda AC, Grammatikakis I, et al. CircInteractome: a web tool for exploring circular RNAs and their interacting proteins and microRNAs. RNA Biol. 2016;13:34–42.

    PubMed  Google Scholar 

  46. Wang J, Gribskov M. IRESpy: an XGBoost model for prediction of internal ribosome entry sites. BMC Bioinformatics. 2019;20:409.

    PubMed  PubMed Central  Google Scholar 

  47. Zhao J, Wu J, Xu T, et al. IRESfinder: identifying RNA internal ribosome entry site in eukaryotic cell using framed K-mer features. J Genet Genomics. 2018;45:403–6.

    PubMed  Google Scholar 

  48. Dominissini D, Moshitch-Moshkovitz S, Schwartz S, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485:201–6.

    CAS  PubMed  Google Scholar 

  49. Molinie B, Giallourakis CC. Genome-wide location analyses of N6-methyladenosine modifications (m6A-Seq). Methods Mol Biol. 2017;1562:45–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Plaza S, Menschaert G, Payre F. In search of lost small peptides. Annu Rev Cell Dev Biol. 2017;33:391–416.

    CAS  PubMed  Google Scholar 

  51. Meng X, Chen Q, Zhang P, et al. CircPro: an integrated tool for the identification of circRNAs with protein-coding potential. Bioinformatics. 2017;33:3314–6.

    CAS  PubMed  Google Scholar 

  52. Sun P, Li G. CircCode: a powerful tool for identifying circRNA coding ability. Front Genet. 2019;10:981.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Spriggs KA, Stoneley M, Bushell M, et al. Reprogramming of translation following cell stress allows IRES-mediated translation to predominate. Biol Cell. 2008;100:27–38.

    CAS  PubMed  Google Scholar 

  54. Wang Y, Wang Z. Efficient backsplicing produces translatable circular mRNAs. RNA. 2015;21:172–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Mo D, Li X, Raabe CA, et al. A universal approach to investigate circRNA protein coding function. Sci Rep. 2019;9:11684.

    PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (Grant number: no. 81602285 and 81872126), Nanjing Medical Science and technique Development Foundation (No. JQX17009).

Author information

Authors and Affiliations

  1. Department of Gynecology, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, No.123, Tianfei Xiang, Mochou Road, Nanjing, 210004, China

    Y. Shi, X. Jia & J. Xu

Authors
  1. Y. Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. X. Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to X. Jia or J. Xu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participations or animals performed by any of the authors.

Informed consent

Informed consent is not required for this type of study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shi, Y., Jia, X. & Xu, J. The new function of circRNA: translation. Clin Transl Oncol 22, 2162–2169 (2020). https://doi.org/10.1007/s12094-020-02371-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-020-02371-1

Keywords

Search

Navigation