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

Dang, Thi Lieu; Le, Cong Truc; Le, Minh Ngoc; Nguyễn, Tùng Lâm; Nguyễn, Thùy Linh; Bao, Sheng; Li, Shaohua; Nguyen, Tuan Anh

doi:10.1038/s42003-020-1071-5

Cited by 18 publications

(14 citation statements)

References 44 publications

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“…m 6 A modification results in increased miR-25-3p to promote pancreatic cancer growth (27). Microprocessor DiGeorge Syndrome Critical Region 8 (DGCR8) processes primary microRNAs (pri-miRNAs) during miRNA biogenesis by interacting with the apical UGU motif of pri-miRNAs (28). m 6 A modification could mark pri-miRNAs for processing by recognizing DGCR8 in a manner dependent on METTL3 or METTL14/m 6 A, suggesting that altered METTL3 or METTL14/m 6 A may contribute to the aberrant expression of miRNAs in a number of biological processes, including cancer (29,30).…”

Section: N6-methyladenosine Upregulates Mir-181d-5p In Exosomes Derived From Cancer-associated Fibroblasts To Inhibit 5-fu Sensitivity Bymentioning

confidence: 99%

N6‑methyladenosine upregulates miR‑181d‑5p in exosomes derived from cancer‑associated fibroblasts to inhibit 5‑FU sensitivity by targeting NCALD in colorectal cancer

Pan

Deng

et al. 2022

Int J Oncol

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Resistance to 5-Fluorouracil (5-FU) is a frequent occurrence in patients with colorectal cancer (CRC). MicroRNAs (miRNAs) from cancer-associated fibroblasts (CAFs)-secreted exosomes have been associated with 5-FU sensitivity. The potential molecular mechanism of CAFs-exosomal miRNAs in CRC remains unclear. The aim of the present study was to elucidate the role of exosomal miRNAs in 5-FU sensitivity in CRC. Exosomes derived from CAFs were extracted. Exosomal miR-181d-5p was identified as a miRNA associated with 5-FU sensitivity. The putative function of exosomal miR-181d-5p was evaluated by ethynyl-2-deoxyuridine staining, flow cytometry, RNA immunoprecipitation, luciferase reporter assay, tumor xenograft formation, reverse transcription-quantitative PCR and western blot analysis. Modification of miR-181d-5p by the RNA N6-methyladenosine (m 6 A) methyltransferase like (METTL)3 was examined by m 6 A methylation analysis. The results indicated that m 6 A modification and METTL3 expression were upregulated in CRC patients. METTL3-dependent m 6 A methylation promoted the miR-181b-5p process by DiGeorge Syndrome Critical Region 8 (DGCR8) in CAFs. CAFs-derived exosomes inhibited 5-FU sensitivity in CRC cells through the METTL3/miR-181d-5p axis. A mechanistic study revealed that miR-181d-5p directly targeted neurocalcin δ (NCALD) to inhibit the 5-FU sensitivity of CRC cells. Patients with higher NCALD levels exhibited a higher survival rate. Taken together, METTL3-dependent m 6 A methylation was upregulated in CRC to promote the processing of miR-181d-5p by DGCR8. This led to increased miR-181d-5p expression, which inhibited the 5-FU sensitivity of CRC cells by targeting NCALD. The results of the present study provided novel insight into exosomal microRNAs in 5-FU sensitivity in CRC cells. Furthermore, exosomal miR-181d-5p may represent a potential prognostic marker for CRC.

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Section: N6-methyladenosine Upregulates Mir-181d-5p In Exosomes Derived From Cancer-associated Fibroblasts To Inhibit 5-fu Sensitivity Bymentioning

confidence: 99%

N6‑methyladenosine upregulates miR‑181d‑5p in exosomes derived from cancer‑associated fibroblasts to inhibit 5‑FU sensitivity by targeting NCALD in colorectal cancer

Pan

Deng

et al. 2022

Int J Oncol

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“…The UGU motif is located at the apical junction strengthening the interaction between DGCR8 and the loop. In this way, it prevents DROSHA from being dislocated at the apical junction and cleaving pri-miRNA at the unproductive sites [ 12 , 14 , 23 , 24 ] (Fig. S1B).…”

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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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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“…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%

“…There are also multiple RNA elements, which prevent DROSHA from residing at the apical junction (Nguyen et al, 2019). For example, a UGU motif in the apical loop enhances the interaction between the loop and DGCR8 (Auyeung et al, 2013;Nguyen et al, 2015;Dang et al, 2020). This interaction is further strengthened by hemin, which is associated with DGCR8 (Partin et al, 2017;Nguyen et al, 2018).…”

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

Cited by 18 publications

References 44 publications

N6‑methyladenosine upregulates miR‑181d‑5p in exosomes derived from cancer‑associated fibroblasts to inhibit 5‑FU sensitivity by targeting NCALD in colorectal cancer

N6‑methyladenosine upregulates miR‑181d‑5p in exosomes derived from cancer‑associated fibroblasts to inhibit 5‑FU sensitivity by targeting NCALD in colorectal cancer

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

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