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

View ORCID ProfileXavier 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, View ORCID ProfileShuo Gu
doi: https://doi.org/10.1101/366492
Xavier Bofill De Ros
National Cancer Institute;
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  • ORCID record for Xavier Bofill De Ros
Wojciech K Kasprzak
Leidos Biomedical Research, Inc.
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Yuba Bhandari
National Cancer Institute;
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Lixin Fan
Leidos Biomedical Research, Inc.
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Quinn Cavanaugh
National Cancer Institute;
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Minjie Jiang
National Cancer Institute;
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Lisheng Dai
National Cancer Institute;
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Acong Yang
National Cancer Institute;
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Tie-Juan Shao
National Cancer Institute;
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Bruce A Shapiro
National Cancer Institute;
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Yun-Xing Wang
National Cancer Institute;
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Shuo Gu
National Cancer Institute;
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  • ORCID record for Shuo Gu
  • For correspondence: shuo.gu@nih.gov
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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.

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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.
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Posted July 10, 2018.
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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
bioRxiv 366492; doi: https://doi.org/10.1101/366492
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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
bioRxiv 366492; doi: https://doi.org/10.1101/366492

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