Flexible pri-miRNA structures enable tunable production of 5' isomiRs

Xavier Bofill-De Ros; Zhenyi Hong; Ben Birkenfeld; Sarangelica Alamo-Ortiz; Acong Yang; Lisheng Dai; Shuo Gu

doi:10.1080/15476286.2022.2025680

Flexible pri-miRNA structures enable tunable production of 5' isomiRs

Xavier Bofill-De Ros^*, Zhenyi Hong, Ben Birkenfeld, Sarangelica Alamo-Ortiz, Acong Yang, Lisheng Dai, Shuo Gu^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

7 Citations (Scopus)

Abstract

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.[Figure: see text].

Original language	English
Journal	RNA Biology
Volume	19
Issue	1
Pages (from-to)	279-289
Number of pages	11
ISSN	1547-6286
DOIs	https://doi.org/10.1080/15476286.2022.2025680 https://doi.org/10.1080/15476286.2022.2025680
Publication status	Published - 2022
Externally published	Yes

Keywords

5’ isomiRs
alternative cleavage
cleavage fidelity
dicer
Drosha
pri-miRNA
RNA structure
RNA-binding proteins

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title = "Flexible pri-miRNA structures enable tunable production of 5' isomiRs",

abstract = "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.[Figure: see text].",

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T1 - Flexible pri-miRNA structures enable tunable production of 5' isomiRs

AU - Bofill-De Ros, Xavier

AU - Hong, Zhenyi

AU - Birkenfeld, Ben

AU - Alamo-Ortiz, Sarangelica

AU - Yang, Acong

AU - Dai, Lisheng

AU - Gu, Shuo

PY - 2022

Y1 - 2022

N2 - 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.[Figure: see text].

AB - 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.[Figure: see text].

KW - 5’ isomiRs

KW - alternative cleavage

KW - cleavage fidelity

KW - dicer

KW - Drosha

KW - pri-miRNA

KW - RNA structure

KW - RNA-binding proteins

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DO - 10.1080/15476286.2022.2025680

M3 - Journal article

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SN - 1547-6286

VL - 19

SP - 279

EP - 289

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ER -

Flexible pri-miRNA structures enable tunable production of 5' isomiRs

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Keywords

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