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Much of our recent work has focused on circular RNAs, which are generated from thousands of protein-coding genes. At some genes, the abundance of the circular RNA exceeds that of the associated linear mRNA by a factor of 10, raising the interesting possibility that the function of some protein-coding genes may be to produce circular noncoding RNAs, not proteins. These circular RNAs are generated when the pre-mRNA splicing machinery “backsplices” and joins a splice donor to an upstream splice acceptor. We showed that repetitive elements, e.g. SINE elements, in the flanking introns are critical determinants of whether the intervening exon(s) circularize. When repeat sequences from the flanking introns base pair to one another, the splice sites are brought into close proximity and backsplicing occurs. This knowledge allowed us to generate plasmids that efficiently produce any circular RNA in species ranging from humans to flies. Using high-throughput screening, we have further shown that the ratio of linear to circular RNA produced from a given gene is modulated by a number of factors, including hnRNPs, SR proteins, core spliceosome, and transcription termination proteins. Surprisingly, when spliceosome components were depleted or inhibited pharmacologically, the steady-state levels of circular RNAs increased while expression of their associated linear mRNAs concomitantly decreased. Inhibition or slowing of canonical pre-mRNA processing events thus shifts the steady-state output of protein-coding genes towards circular RNAs, which likely helps explain why and how circular RNAs show tissue-specific expression profiles. Once generated, we showed that most circular RNAs are exported to the cytoplasm using a length-dependent and evolutionarily conserved pathway. It still remains largely unclear what most circular RNAs do, although two are known to efficiently modulate the activity of microRNAs. Ongoing efforts aim to further elucidate the mechanisms by which circular RNAs are produced, regulated, and function to control cell physiology and impact human diseases.
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Papers共 80 篇Author StatisticsCo-AuthorSimilar Experts
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Methods in molecular biology (Clifton, N.J.) (2024): 3-19
Journal of Biological Chemistryno. 3 (2024)
Bradley W Wright,Jeremy E Wilusz
Genes & developmentno. 7-8 (2024): 291-293
CANCERSno. 5 (2024)
Jasmin Morandell,Alan Monziani, Martina Lazioli,Deborah Donzel,Jessica Doring,Claudio Oss Pegorar,Angela D'Anzi,Miguel Pellegrini, Andrea Mattiello, Dalia Bortolotti,Guendalina Bergonzoni,Takshashila Tripathi,Virginia B. Mattis,Marina Kovalenko, Jessica Rosati,Christoph Dieterich,Erik Dassi,Vanessa C. Wheeler,Zdenka Ellederova,Jeremy E. Wilusz,Gabriella Viero,Marta Biagioli
MOLECULAR THERAPY NUCLEIC ACIDSno. 3 (2024)
bioRxiv the preprint server for biology (2024)
NUCLEIC ACIDS RESEARCHno. 6 (2024): 3358-3374
Molecular cellno. 19 (2024): 3843-3859.e8
John S. S. Mattick,Paulo P. P. Amaral,Piero Carninci,Susan Carpenter,Howard Y. Y. Chang,Ling-Ling Chen,Runsheng Chen,Caroline Dean,Marcel E. E. Dinger, Katherine A. A. Fitzgerald,Thomas R. R. Gingeras,Mitchell Guttman,Tetsuro Hirose,Maite Huarte,Rory Johnson,Chandrasekhar Kanduri,Philipp Kapranov,Jeanne B. B. Lawrence,Jeannie T. T. Lee,Joshua T. T. Mendell,Timothy R. R. Mercer,Kathryn J. J. Moore,Shinichi Nakagawa,John L. L. Rinn,David L. L. Spector,Igor Ulitsky,Yue Wan,Jeremy E. E. Wilusz,Mian Wu
bioRxiv the preprint server for biology (2023)
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#Papers: 80
#Citation: 10935
H-Index: 34
G-Index: 80
Sociability: 6
Diversity: 0
Activity: 1
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