Mismatched and wobble base pairs govern primary microRNA processing by human Microprocessor

Li, Shaohua; Nguyễn, Tùng Lâm; Nguyễn, Thùy Linh; Nguyen, Tuan Anh

doi:10.1038/s41467-020-15674-2

Cited by 45 publications

(68 citation statements)

References 49 publications

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“…The effect of bulges in the midB_1013 is similar to that of mismatches and wobble base pairs found in the previous study [19]. Therefore, we examined the effect of bulges in Bar charts to show the unproductive/productive ratios or cleavage efficiency (i.e.…”

Section: The Midb_89 On the 3p-strand Influences The Cleavage Sites Osupporting

confidence: 57%

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Bulges control pri-miRNA processing in a position and strand-dependent manner

Nguyễn

et al. 2020

RNA Biology

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MicroRNAs (miRNAs) play critical roles in gene expression and numerous human diseases. The success of miRNA biogenesis is largely determined by the primary miRNA (pri-miRNA) processing by the DROSHA-DGCR8 complex, called Microprocessor. Here, we analysed the high-throughput pri-miRNA processing assays and secondary structures of pri-miRNAs to investigate the roles of bulges in the pri-miRNA processing. We found that bulges in multiple places control both the cleavage efficiency and accuracy of pri-miRNA processing. These bulges were shown to act on Microprocessor via its catalytic subunit, DROSHA, and function in a position and strand-dependent manner. Interestingly, we discovered that the enriched and conserved bulges, called midB, can correct DROSHA orientation on pri-miRNAs, thereby enhancing production of miRNAs. The revealed functions of the bulges help improve our understanding of pri-miRNA processing and suggest their potential roles in miRNA biogenesis regulation.

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Section: The Midb_89 On the 3p-strand Influences The Cleavage Sites Osupporting

confidence: 57%

“…S1A). Microprocessor interacts with multiple RNA elements within pri-miRNAs in order to ensure that its double cleavage occurs both accurately and efficiently [12][13][14][15][16][17][18][19][20]. These RNA elements can be classified into two groups, primary RNA sequencing motifs and secondary RNA structures.…”

Section: Introductionmentioning

confidence: 99%

Bulges control pri-miRNA processing in a position and strand-dependent manner

Nguyễn

et al. 2020

RNA Biology

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“…Multiple RNA elements (including UG, UGU, mGHG, seedMW, midMW, CNNC, and AIL), are known to affect the cleavage state of Microprocessor via either DROSHA or DGCR8 (Auyeung et al, 2013;Fang and Bartel, 2015;Nguyen et al, 2015;Kim et al, 2018;Nguyen et al, 2018;Kwon et al, 2019;Nguyen et al, 2019;Dang et al, 2020;Li et al, 2020;Nguyen et al, 2020). We have previously demonstrated that the action of an RNA element is dependent on its position.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of DGCR8 at the loop also prevents DROSHA from interacting with the apical junction. In addition, a midMW, which is frequently present in the upper stem of human pri-miRNAs, inhibits the unproductive cleavage by DROSHA (Li et al, 2020). The inhibition of unproductive cleavage by these mechanisms increases the chance of productive cleavages by Microprocessor.…”

Section: Introductionmentioning

confidence: 99%

Human disease-associated single nucleotide polymorphism changes the orientation of DROSHA on pri-mir-146a

Nguyễn

et al. 2020

RNA

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The Microprocessor complex of DROSHA and DGCR8 initiates the biosynthesis of microRNAs (miRNAs) by processing primary miRNAs (pri-miRNAs). Microprocessor can be oriented on pri-miRNAs in opposite directions to generate productive and unproductive cleavages at their basal and apical junctions, respectively. However, only the productive cleavage gives rise to miRNAs. A single nucleotide polymorphism (SNP, rs2910164) in pri-mir-146a is associated with various human diseases. Although this SNP was found to reduce the expression of miRNA, it is still not known if it affects the activity of Microprocessor directly, and how it functions. In this study, we revealed that the SNP created an unexpected mGHG motif at the apical junction of pri-mir-146a. This mGHG motif interacted with the double-stranded RNA-binding domain (dsRBD) of DROSHA, switching its orientation on pri-mir-146a from the basal to the apical junction. As a result, the SNP facilitated Microprocessor to cleave SNP-pri-mir-146a at its unproductive sites. Our findings help to elucidate the molecular mechanism that explains how the diseaseassociated SNP modulates the biogenesis of pri-mir-146a and thereby affects its cellular functions.

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“…The apical loop connects to one end of the stem via the apical junction, whereas two ssRNA segments, namely the 5p-and 3p-basal segments, flank the other end, making a basal junction 2,15 . Pri-miRNAs contain several RNA elements, such as UG, UGU, mGHG, CNNC, seedMW, and midMW, which are critical for the efficiency and accuracy of pri-miRNA processing by Microprocessor 8,10,17,[22][23][24][25][26][27][28] . The recent report demonstrated that the internal loop in the lower stem of pri-miRNAs facilitates the single cleavage of pri-miRNAs on the 5p-strand and reduces the double cleavages of Microprocessor, thereby controlling miRNA biogenesis 29 .…”

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confidence: 99%

Select amino acids in DGCR8 are essential for the UGU-pri-miRNA interaction and processing

Dang

et al. 2020

Commun Biol

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Microprocessor, composed of DROSHA and DGCR8, processes primary microRNAs (pri-miRNAs) in miRNA biogenesis. Its cleavage efficiency and accuracy are enhanced because DGCR8 interacts with the apical UGU motif of pri-miRNAs. However, the mechanism and influence of DGCR8-UGU interaction on cellular miRNA expression are still elusive. In this study, we demonstrated that Rhed (i.e., the RNA-binding heme domain, amino acids 285-478) of DGCR8 interacts with UGU. In addition, we identified three amino acids 461-463 in Rhed, which are critical for the UGU interaction and essential for Microprocessor to accurately and efficiently process UGU-pri-miRNAs in vitro and UGU-miRNA expression in human cells. Furthermore, we found that within the DGCR8 dimer, the amino acids 461-463 from one monomer are capable of discriminating between UGU-and noUGU-pri-miRNAs. Our findings improve the current understanding of the substrate-recognizing mechanism of DGCR8 and implicate the roles of this recognition in differentiating miRNA expression in human cells.

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Mismatched and wobble base pairs govern primary microRNA processing by human Microprocessor

Cited by 45 publications

References 49 publications

Bulges control pri-miRNA processing in a position and strand-dependent manner

Bulges control pri-miRNA processing in a position and strand-dependent manner

Human disease-associated single nucleotide polymorphism changes the orientation of DROSHA on pri-mir-146a

Select amino acids in DGCR8 are essential for the UGU-pri-miRNA interaction and processing

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