@article{acf5fef581b7420bb737a1939b979fa8,
title = "Structured elements drive extensive circular RNA translation",
abstract = "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.",
keywords = "18S complementarity, cap-independent translation, circFGFR1p, circRNA-encoded protein, circular RNA, FGFR1, internal ribosome entry site, structured RNA element",
author = "Chen, {Chun Kan} and Ran Cheng and Janos Demeter and Jin Chen and Shira Weingarten-Gabbay and Lihua Jiang and Snyder, {Michael P.} and Weissman, {Jonathan S.} and Eran Segal and Jackson, {Peter K.} and Chang, {Howard Y.}",
note = "Funding Information: We thank Dr. Peter Sarnow and Dr. Kuo-Feng Weng for assisting the polysome profiling experiments, Dr. Rhiju Das and Ved Topkar for helping the M2-seq and M2-net analyses, and Dr. Matthias Mann and Dr. Andreas-David Brunner for the MS analytical pipeline. Cell sorting/flow cytometry analysis was done in the Stanford Shared FACS Facility. Imaging was done in the Stanford Cell Sciences Imaging Facility. MS was done at Stanford University Mass Spectrometry. J.C. is funded by the NIH K99/R00 Pathway to Independence Award ( K99-GM134154 ). J.S.W. is an Investigator of the Howard Hughes Medical Institute. C.-K.C. is supported by the Helen Hay Whitney Foundation Fellowship. This work was funded by the NIH ( R01-HG004361 , RM1-HG007735 , and R35-CA209919 to H.Y.C. and R01-CA250534 to P.K.J.). H.Y.C. is an Investigator of the Howard Hughes Medical Institute. Funding Information: We thank Dr. Peter Sarnow and Dr. Kuo-Feng Weng for assisting the polysome profiling experiments, Dr. Rhiju Das and Ved Topkar for helping the M2-seq and M2-net analyses, and Dr. Matthias Mann and Dr. Andreas-David Brunner for the MS analytical pipeline. Cell sorting/flow cytometry analysis was done in the Stanford Shared FACS Facility. Imaging was done in the Stanford Cell Sciences Imaging Facility. MS was done at Stanford University Mass Spectrometry. J.C. is funded by the NIH K99/R00 Pathway to Independence Award (K99-GM134154). J.S.W. is an Investigator of the Howard Hughes Medical Institute. C.-K.C. is supported by the Helen Hay Whitney Foundation Fellowship. This work was funded by the NIH (R01-HG004361, RM1-HG007735, and R35-CA209919 to H.Y.C. and R01-CA250534 to P.K.J.). H.Y.C. is an Investigator of the Howard Hughes Medical Institute. C.-K.C. led the project, performed experiments, and analyzed data. R.C. performed and analyzed the PRM-MS experiments. J.D. J.C. and L.J. helped analyze the MS/MS peptidomic datasets. M.P.S. J.S.W. and P.K.J. supervised the MS/MS analyses and provided key suggestions. S.W.-G. and E.S. provided the oligo library and helped develop the IRES reporter screening assay. H.Y.C. conceived and supervised the entire project. C.-K.C. and H.Y.C. wrote the manuscript with input from all authors. Stanford University has filed patent applications on the basis of this work, and H.Y.C. and C.-K.C. are named as co-inventors. H.Y.C. is a co-founder and advisor of Accent Therapeutics, Boundless Bio, Cartography Biosciences, and Circ Bio. H.Y.C. is an advisor of 10X Genomics, Arsenal Biosciences, and Spring Discovery. H.Y.C. is a member of the Molecular Cell advisory board. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = oct,
day = "21",
doi = "10.1016/j.molcel.2021.07.042",
language = "English (US)",
volume = "81",
pages = "4300--4318.e13",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "20",
}