Structured elements drive extensive circular RNA translation

Chun Kan Chen, Ran Cheng, Janos Demeter, Jin Chen, Shira Weingarten-Gabbay, Lihua Jiang, Michael P. Snyder, Jonathan S. Weissman, Eran Segal, Peter K. Jackson, Howard Y. Chang

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


The human genome encodes tens of thousands circular RNAs (circRNAs) with mostly unknown functions. Circular RNAs require internal ribosome entry sites (IRES) if they are to undergo translation without a 5′ cap. Here, we develop a high-throughput screen to systematically discover RNA sequences that can direct circRNA translation in human cells. We identify more than 17,000 endogenous and synthetic sequences as candidate circRNA IRES. 18S rRNA complementarity and a structured RNA element positioned on the IRES are important for driving circRNA translation. Ribosome profiling and peptidomic analyses show extensive IRES-ribosome association, hundreds of circRNA-encoded proteins with tissue-specific distribution, and antigen presentation. We find that circFGFR1p, a protein encoded by circFGFR1 that is downregulated in cancer, functions as a negative regulator of FGFR1 oncoprotein to suppress cell growth during stress. Systematic identification of circRNA IRES elements may provide important links among circRNA regulation, biological function, and disease.

Original languageEnglish (US)
Pages (from-to)4300-4318.e13
JournalMolecular cell
Issue number20
StatePublished - Oct 21 2021


  • 18S complementarity
  • FGFR1
  • cap-independent translation
  • circFGFR1p
  • circRNA-encoded protein
  • circular RNA
  • internal ribosome entry site
  • structured RNA element

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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