Extensive translation of circular RNAs driven by N6-methyladenosine

By Yun Yang, Xiaojuan Fan, Miaowei Mao, Xiaowei Song, Ping Wu, Yang Zhang, Yongfeng Jin, Yi Yang, Ling-Ling Chen, Yang Wang and 3 more. Cell Research, 2017

1,649 citations recorded by the source corpus.

Extensive pre-mRNA back-splicing generates numerous circular RNAs (circRNAs) in human transcriptome. However, the biological functions of these circRNAs remain largely unclear. Here we report that N6-methyladenosine (m6A), the most abundant base modification of RNA, promotes efficient initiation of protein translation from circRNAs in human cells. We discover that consensus m6A motifs are enriched in circRNAs and a single m6A site is sufficient to drive translation initiation. This m6A-driven translation requires initiation factor eIF4G2 and m6A reader YTHDF3, and is enhanced by methyltransferase METTL3/14, inhibited by demethylase FTO, and upregulated upon heat shock. Further analyses through polysome profiling, computational prediction and mass spectrometry reveal that m6A-driven translation of circRNAs is widespread, with hundreds of endogenous circRNAs having translation potential. Our study expands the coding landscape of human transcriptome, and suggests a role of circRNA-derived proteins in cellular responses to environmental stress.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/451bcef91df96e6d1d014ddeae0e524d7d1a57d0

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In Molecular Biology

1. George A. Calin
2. M. Ferracin
3. Wanying Wu
4. Peifeng Ji
5. Kinga Nemeth
6. R. Bayraktar
7. Fangqing Zhao
8. Stas Wüst

Citations in the corpus

• Functions of N6-methyladenosine and its role in cancer (2019, background): “Type Regulator Function Reference m6A writer METTL3 catalyzes m6A modification [13, 14] METTL14 helps METTL3 to recognize the subtract [13, 14] METTL16 catalyzes m6A modification [15] RBM15 binds the m6A complex and recruit it to special RNA site [16, 17] VIRMA recruits the m6A complex to the specia”
• Circular RNA: metabolism, functions and interactions with proteins (2020, background): “In addition to previously described m6A-mediated translation [39, 64, 81], artificial [67] and endogenous circRNAs containing an internal ribosome entry site (IRES) that directly recruits ribosomes [82], can also be translated [63].”
• Circular RNA-protein interactions: functions, mechanisms, and identification (2020, background): “abundant base modification of RNA, can promote efficient initiation of protein translation from circRNAs in human cells [107].”
• The potential role of RNA N6-methyladenosine in Cancer progression (2020, background): “Shi H, Wang X, Lu Z, Zhao BS, Ma H, Hsu PJ, Liu C, He C. YTHDF3 facilitates translation and decay of N-methyladenosine-modified RNA.”
• Circular RNAs: Promising Biomarkers for Human Diseases (2018, background): “N(6)-methyladenosine can promote the initiation of protein translation from circRNA in human cells, and a single N(6)-methyladenosine residue in circRNA is sufficient to drive the translation [29].”
• Circbank: a comprehensive database for circRNA with standard nomenclature (2019, background): “In addition to IRESs, m 6 A modification can also promote the initiation of protein translation from circRNA in human cells [26].”
• CircAtlas: an integrated resource of one million highly accurate circular RNAs from 1070 vertebrate transcriptomes (2020, background): “A more recent study has revealed that N 6 -methyladenosine (m 6 A) [11] promotes the efficient initiation of protein translation from the circRNAs.”
• Non-coding RNAs in disease: from mechanisms to therapeutics (2023, positive): “Through their roles in development, apoptosis, stress responses and cell cycle regulation, circRNA-encoded peptides could be important in cancer initiation and progression 94 .”