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Alternative cleavage and polyadenylation generates downstream uncapped RNA isoforms with translation potential

The use of alternative promoters, splicing, and cleavage and polyadenylation (APA) generates mRNA isoforms that expand the diversity and complexity of the transcriptome. Here, we uncovered thousands of previously undescribed 5′ uncapped and polyadenylated transcripts (5′ UPTs). We show that these tr...

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Autores principales: Malka, Yuval, Alkan, Ferhat, Ju, Shinyeong, Körner, Pierre-Rene, Pataskar, Abhijeet, Shulman, Eldad, Loayza-Puch, Fabricio, Champagne, Julien, Wenzel, Casper, Faller, William James, Elkon, Ran, Lee, Cheolju, Agami, Reuven
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9636002/
https://www.ncbi.nlm.nih.gov/pubmed/36270248
http://dx.doi.org/10.1016/j.molcel.2022.09.036
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author Malka, Yuval
Alkan, Ferhat
Ju, Shinyeong
Körner, Pierre-Rene
Pataskar, Abhijeet
Shulman, Eldad
Loayza-Puch, Fabricio
Champagne, Julien
Wenzel, Casper
Faller, William James
Elkon, Ran
Lee, Cheolju
Agami, Reuven
author_facet Malka, Yuval
Alkan, Ferhat
Ju, Shinyeong
Körner, Pierre-Rene
Pataskar, Abhijeet
Shulman, Eldad
Loayza-Puch, Fabricio
Champagne, Julien
Wenzel, Casper
Faller, William James
Elkon, Ran
Lee, Cheolju
Agami, Reuven
author_sort Malka, Yuval
collection PubMed
description The use of alternative promoters, splicing, and cleavage and polyadenylation (APA) generates mRNA isoforms that expand the diversity and complexity of the transcriptome. Here, we uncovered thousands of previously undescribed 5′ uncapped and polyadenylated transcripts (5′ UPTs). We show that these transcripts resist exonucleases due to a highly structured RNA and N6-methyladenosine modification at their 5′ termini. 5′ UPTs appear downstream of APA sites within their host genes and are induced upon APA activation. Strong enrichment in polysomal RNA fractions indicates 5′ UPT translational potential. Indeed, APA promotes downstream translation initiation, non-canonical protein output, and consistent changes to peptide presentation at the cell surface. Lastly, we demonstrate the biological importance of 5′ UPTs using Bcl2, a prominent anti-apoptotic gene whose entire coding sequence is a 5′ UPT generated from 5′ UTR-embedded APA sites. Thus, APA is not only accountable for terminating transcripts, but also for generating downstream uncapped RNAs with translation potential and biological impact.
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spelling pubmed-96360022022-11-07 Alternative cleavage and polyadenylation generates downstream uncapped RNA isoforms with translation potential Malka, Yuval Alkan, Ferhat Ju, Shinyeong Körner, Pierre-Rene Pataskar, Abhijeet Shulman, Eldad Loayza-Puch, Fabricio Champagne, Julien Wenzel, Casper Faller, William James Elkon, Ran Lee, Cheolju Agami, Reuven Mol Cell Article The use of alternative promoters, splicing, and cleavage and polyadenylation (APA) generates mRNA isoforms that expand the diversity and complexity of the transcriptome. Here, we uncovered thousands of previously undescribed 5′ uncapped and polyadenylated transcripts (5′ UPTs). We show that these transcripts resist exonucleases due to a highly structured RNA and N6-methyladenosine modification at their 5′ termini. 5′ UPTs appear downstream of APA sites within their host genes and are induced upon APA activation. Strong enrichment in polysomal RNA fractions indicates 5′ UPT translational potential. Indeed, APA promotes downstream translation initiation, non-canonical protein output, and consistent changes to peptide presentation at the cell surface. Lastly, we demonstrate the biological importance of 5′ UPTs using Bcl2, a prominent anti-apoptotic gene whose entire coding sequence is a 5′ UPT generated from 5′ UTR-embedded APA sites. Thus, APA is not only accountable for terminating transcripts, but also for generating downstream uncapped RNAs with translation potential and biological impact. Cell Press 2022-10-20 /pmc/articles/PMC9636002/ /pubmed/36270248 http://dx.doi.org/10.1016/j.molcel.2022.09.036 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Malka, Yuval
Alkan, Ferhat
Ju, Shinyeong
Körner, Pierre-Rene
Pataskar, Abhijeet
Shulman, Eldad
Loayza-Puch, Fabricio
Champagne, Julien
Wenzel, Casper
Faller, William James
Elkon, Ran
Lee, Cheolju
Agami, Reuven
Alternative cleavage and polyadenylation generates downstream uncapped RNA isoforms with translation potential
title Alternative cleavage and polyadenylation generates downstream uncapped RNA isoforms with translation potential
title_full Alternative cleavage and polyadenylation generates downstream uncapped RNA isoforms with translation potential
title_fullStr Alternative cleavage and polyadenylation generates downstream uncapped RNA isoforms with translation potential
title_full_unstemmed Alternative cleavage and polyadenylation generates downstream uncapped RNA isoforms with translation potential
title_short Alternative cleavage and polyadenylation generates downstream uncapped RNA isoforms with translation potential
title_sort alternative cleavage and polyadenylation generates downstream uncapped rna isoforms with translation potential
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9636002/
https://www.ncbi.nlm.nih.gov/pubmed/36270248
http://dx.doi.org/10.1016/j.molcel.2022.09.036
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