Structural differences between pri-miRNA paralogs promotes alternative Drosha cleavage and expands target repertoires

Xavier Bofill De Ros; Wojciech K. Kasprzak; Yuba Bhandari; Lixin Fan; Quinn Cavanaugh; Minjie Jiang; Lisheng Dai; Acong Yang; Tie Juan Shao; Bruce A. Shapiro; Yun Xing Wang; Shuo Gu

doi:10.1101/366492

Structural differences between pri-miRNA paralogs promotes alternative Drosha cleavage and expands target repertoires

Xavier Bofill De Ros, Wojciech K. Kasprzak, Yuba Bhandari, Lixin Fan, Quinn Cavanaugh, Minjie Jiang, Lisheng Dai, Acong Yang, Tie Juan Shao, Bruce A. Shapiro, Yun Xing Wang, Shuo Gu

Research output: Contribution to journal › Article › peer-review

Abstract

MicroRNA (miRNA) processing begins with Drosha cleavage, the fidelity of which is critical for downstream processing and mature miRNA target specificity. To understand how pri-miRNA sequence and structure influence Drosha cleavage, we studied the maturation of three pri-miR-9 paralogs, which encode the same mature miRNA but differ in the surrounding scaffold. We show that pri-miR-9-1 has a unique Drosha cleavage profile due to its distorted and flexible stem structure. Cleavage of pri-miR-9-1, but not pri-miR-9-2 or pri-miR-9-3, generates an alternative-miR-9 with a shifted seed sequence that expands the scope of its target RNAs. Analyses of low grade glioma patient samples indicate that the alternative-miR-9 plays a distinct role in preventing tumor progression. To generalize our model, we provide evidence that distortion of pri-miRNA stems correlates with Drosha cleavage at non-canonical sites. Our studies reveal that pri-miRNA paralogs can have distinct functions via differential Drosha processing.

Original language	English (US)
Journal	Unknown Journal
DOIs	https://doi.org/10.1101/366492
State	Published - Jul 10 2018
Externally published	Yes

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
Immunology and Microbiology(all)
Neuroscience(all)
Pharmacology, Toxicology and Pharmaceutics(all)

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Structural differences between pri-miRNA paralogs promotes alternative Drosha cleavage and expands target repertoires. / Ros, Xavier Bofill De; Kasprzak, Wojciech K.; Bhandari, Yuba; Fan, Lixin; Cavanaugh, Quinn; Jiang, Minjie; Dai, Lisheng; Yang, Acong; Shao, Tie Juan; Shapiro, Bruce A.; Wang, Yun Xing; Gu, Shuo.

In: Unknown Journal, 10.07.2018.

Research output: Contribution to journal › Article › peer-review

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title = "Structural differences between pri-miRNA paralogs promotes alternative Drosha cleavage and expands target repertoires",

abstract = "MicroRNA (miRNA) processing begins with Drosha cleavage, the fidelity of which is critical for downstream processing and mature miRNA target specificity. To understand how pri-miRNA sequence and structure influence Drosha cleavage, we studied the maturation of three pri-miR-9 paralogs, which encode the same mature miRNA but differ in the surrounding scaffold. We show that pri-miR-9-1 has a unique Drosha cleavage profile due to its distorted and flexible stem structure. Cleavage of pri-miR-9-1, but not pri-miR-9-2 or pri-miR-9-3, generates an alternative-miR-9 with a shifted seed sequence that expands the scope of its target RNAs. Analyses of low grade glioma patient samples indicate that the alternative-miR-9 plays a distinct role in preventing tumor progression. To generalize our model, we provide evidence that distortion of pri-miRNA stems correlates with Drosha cleavage at non-canonical sites. Our studies reveal that pri-miRNA paralogs can have distinct functions via differential Drosha processing.",

author = "Ros, {Xavier Bofill De} and Kasprzak, {Wojciech K.} and Yuba Bhandari and Lixin Fan and Quinn Cavanaugh and Minjie Jiang and Lisheng Dai and Acong Yang and Shao, {Tie Juan} and Shapiro, {Bruce A.} and Wang, {Yun Xing} and Shuo Gu",

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year = "2018",

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doi = "10.1101/366492",

language = "English (US)",

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AU - Ros, Xavier Bofill De

AU - Kasprzak, Wojciech K.

AU - Bhandari, Yuba

AU - Fan, Lixin

AU - Cavanaugh, Quinn

AU - Jiang, Minjie

AU - Dai, Lisheng

AU - Yang, Acong

AU - Shao, Tie Juan

AU - Shapiro, Bruce A.

AU - Wang, Yun Xing

AU - Gu, Shuo

N1 - Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2018/7/10

Y1 - 2018/7/10

N2 - MicroRNA (miRNA) processing begins with Drosha cleavage, the fidelity of which is critical for downstream processing and mature miRNA target specificity. To understand how pri-miRNA sequence and structure influence Drosha cleavage, we studied the maturation of three pri-miR-9 paralogs, which encode the same mature miRNA but differ in the surrounding scaffold. We show that pri-miR-9-1 has a unique Drosha cleavage profile due to its distorted and flexible stem structure. Cleavage of pri-miR-9-1, but not pri-miR-9-2 or pri-miR-9-3, generates an alternative-miR-9 with a shifted seed sequence that expands the scope of its target RNAs. Analyses of low grade glioma patient samples indicate that the alternative-miR-9 plays a distinct role in preventing tumor progression. To generalize our model, we provide evidence that distortion of pri-miRNA stems correlates with Drosha cleavage at non-canonical sites. Our studies reveal that pri-miRNA paralogs can have distinct functions via differential Drosha processing.

AB - MicroRNA (miRNA) processing begins with Drosha cleavage, the fidelity of which is critical for downstream processing and mature miRNA target specificity. To understand how pri-miRNA sequence and structure influence Drosha cleavage, we studied the maturation of three pri-miR-9 paralogs, which encode the same mature miRNA but differ in the surrounding scaffold. We show that pri-miR-9-1 has a unique Drosha cleavage profile due to its distorted and flexible stem structure. Cleavage of pri-miR-9-1, but not pri-miR-9-2 or pri-miR-9-3, generates an alternative-miR-9 with a shifted seed sequence that expands the scope of its target RNAs. Analyses of low grade glioma patient samples indicate that the alternative-miR-9 plays a distinct role in preventing tumor progression. To generalize our model, we provide evidence that distortion of pri-miRNA stems correlates with Drosha cleavage at non-canonical sites. Our studies reveal that pri-miRNA paralogs can have distinct functions via differential Drosha processing.

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