Flexible pri-miRNA structures enable tunable production of 5’ isomiRs
The Drosha cleavage of a pri-miRNA defines mature microRNA sequence. Drosha cleavage at alternative positions generates 5’ isoforms (isomiRs) which have distinctive functions. To understand how pri-miRNA structures influence Drosha cleavage, we performed a systematic analysis of the maturation of en...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | RNA Biology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15476286.2022.2025680 |
| _version_ | 1797403955156746240 |
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| author | Xavier Bofill-De Ros Zhenyi Hong Ben Birkenfeld Sarangelica Alamo-Ortiz Acong Yang Lisheng Dai Shuo Gu |
| author_facet | Xavier Bofill-De Ros Zhenyi Hong Ben Birkenfeld Sarangelica Alamo-Ortiz Acong Yang Lisheng Dai Shuo Gu |
| author_sort | Xavier Bofill-De Ros |
| collection | DOAJ |
| description | The Drosha cleavage of a pri-miRNA defines mature microRNA sequence. Drosha cleavage at alternative positions generates 5’ isoforms (isomiRs) which have distinctive functions. To understand how pri-miRNA structures influence Drosha cleavage, we performed a systematic analysis of the maturation of endogenous pri-miRNAs and their variants both in vitro and in vivo. We show that in addition to previously known features, the overall structural flexibility of pri-miRNA impact Drosha cleavage fidelity. Internal loops and nearby G · U wobble pairs on the pri-miRNA stem induce the use of non-canonical cleavage sites by Drosha, resulting in 5’ isomiR production. By analysing patient data deposited in the Cancer Genome Atlas, we provide evidence that alternative Drosha cleavage of pri-miRNAs is a tunable process that responds to the level of pri-miRNA-associated RNA-binding proteins. Together, our findings reveal that Drosha cleavage fidelity can be modulated by altering pri-miRNA structure, a potential mechanism underlying 5’ isomiR biogenesis in tumours. Graphical Abstract |
| first_indexed | 2024-03-09T02:47:07Z |
| format | Article |
| id | doaj.art-323a20767c8b455ebfa77ffc7863939f |
| institution | Directory Open Access Journal |
| issn | 1547-6286 1555-8584 |
| language | English |
| last_indexed | 2024-03-09T02:47:07Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | RNA Biology |
| spelling | doaj.art-323a20767c8b455ebfa77ffc7863939f2023-12-05T16:09:51ZengTaylor & Francis GroupRNA Biology1547-62861555-85842022-12-0119127928910.1080/15476286.2022.20256802025680Flexible pri-miRNA structures enable tunable production of 5’ isomiRsXavier Bofill-De Ros0Zhenyi Hong1Ben Birkenfeld2Sarangelica Alamo-Ortiz3Acong Yang4Lisheng Dai5Shuo Gu6RNA Biology Laboratory, Center for Cancer Research, National Cancer InstituteMouse Cancer Genetics Program, Center for Cancer Research, National Cancer InstituteRNA Biology Laboratory, Center for Cancer Research, National Cancer InstituteRNA Biology Laboratory, Center for Cancer Research, National Cancer InstituteRNA Biology Laboratory, Center for Cancer Research, National Cancer InstituteRNA Biology Laboratory, Center for Cancer Research, National Cancer InstituteRNA Biology Laboratory, Center for Cancer Research, National Cancer InstituteThe Drosha cleavage of a pri-miRNA defines mature microRNA sequence. Drosha cleavage at alternative positions generates 5’ isoforms (isomiRs) which have distinctive functions. To understand how pri-miRNA structures influence Drosha cleavage, we performed a systematic analysis of the maturation of endogenous pri-miRNAs and their variants both in vitro and in vivo. We show that in addition to previously known features, the overall structural flexibility of pri-miRNA impact Drosha cleavage fidelity. Internal loops and nearby G · U wobble pairs on the pri-miRNA stem induce the use of non-canonical cleavage sites by Drosha, resulting in 5’ isomiR production. By analysing patient data deposited in the Cancer Genome Atlas, we provide evidence that alternative Drosha cleavage of pri-miRNAs is a tunable process that responds to the level of pri-miRNA-associated RNA-binding proteins. Together, our findings reveal that Drosha cleavage fidelity can be modulated by altering pri-miRNA structure, a potential mechanism underlying 5’ isomiR biogenesis in tumours. Graphical Abstracthttp://dx.doi.org/10.1080/15476286.2022.2025680droshadicercleavage fidelityalternative cleavage5’ isomirspri-mirnarna structurerna-binding proteins |
| spellingShingle | Xavier Bofill-De Ros Zhenyi Hong Ben Birkenfeld Sarangelica Alamo-Ortiz Acong Yang Lisheng Dai Shuo Gu Flexible pri-miRNA structures enable tunable production of 5’ isomiRs RNA Biology drosha dicer cleavage fidelity alternative cleavage 5’ isomirs pri-mirna rna structure rna-binding proteins |
| title | Flexible pri-miRNA structures enable tunable production of 5’ isomiRs |
| title_full | Flexible pri-miRNA structures enable tunable production of 5’ isomiRs |
| title_fullStr | Flexible pri-miRNA structures enable tunable production of 5’ isomiRs |
| title_full_unstemmed | Flexible pri-miRNA structures enable tunable production of 5’ isomiRs |
| title_short | Flexible pri-miRNA structures enable tunable production of 5’ isomiRs |
| title_sort | flexible pri mirna structures enable tunable production of 5 isomirs |
| topic | drosha dicer cleavage fidelity alternative cleavage 5’ isomirs pri-mirna rna structure rna-binding proteins |
| url | http://dx.doi.org/10.1080/15476286.2022.2025680 |
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