N6-methyl-adenosine (m6A) marks primary microRNAs for processing

By Claudio R. Alarcón, Hyeseung Lee, H. Goodarzi, Nils Halberg, S. Tavazoie. Nature, 2015

1,243 citations recorded by the source corpus.

The first step in the biogenesis of microRNAs is the processing of primary microRNAs (pri-miRNAs) by the microprocessor complex, composed of the RNA-binding protein DGCR8 and the type III RNase DROSHA. This initial event requires recognition of the junction between the stem and the flanking single-stranded RNA of the pri-miRNA hairpin by DGCR8 followed by recruitment of DROSHA, which cleaves the RNA duplex to yield the pre-miRNA product. While the mechanisms underlying pri-miRNA processing have been determined, the mechanism by which DGCR8 recognizes and binds pri-miRNAs, as opposed to other secondary structures present in transcripts, is not understood. Here we find in mammalian cells that methyltransferase-like 3 (METTL3) methylates pri-miRNAs, marking them for recognition and processing by DGCR8. Consistent with this, METTL3 depletion reduced the binding of DGCR8 to pri-miRNAs and resulted in the global reduction of mature miRNAs and concomitant accumulation of unprocessed pri-miRNAs. In vitro processing reactions confirmed the sufficiency of the N6-methyladenosine (m6A) mark in promoting pri-miRNA processing. Finally, gain-of-function experiments revealed that METTL3 is sufficient to enhance miRNA maturation in a global and non-cell-type-specific manner. Our findings reveal that the m6A mark acts as a key post-transcriptional modification that promotes the initiation of miRNA biogenesis.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/795394273bd2b2afd37ba67511a121062c718fd7

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In Cancer Research

1. Chuan He
2. Y. Yue
3. Jianzhao Liu
4. Kate D. Meyer
5. Samie R. Jaffrey
6. Yuan Zhou
7. Qinghua Cui
8. Pan Zeng

In Molecular Biology

1. Chuan He
2. Samie R. Jaffrey
3. Hailing Shi
4. Kate D. Meyer
5. Jianzhao Liu
6. Y. Yue
7. Jiangbo W
8. Jianjun Chen

Citations in the corpus

• Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA (2016, background): “In human cells, thousands of mRNAs are subject to m(6)A modification (28, 29), which has been implicated in mRNA splicing, nuclear export, and translation (31) as well as microRNA processing (32).”
• Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia (2019, background): “, 2015b), primary microRNA processing (Alarcon et al., 2015), and protein-RNA interactions (Liu et al.”
• Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism (2018, background): “Specially, HNRNPA2B1 has been reported to directly bind to m(6)A, leading to the regulation of alternative splicing events similar to those regulated by METTL3,(104) as well as facilitating the processing of primary microRNAs (pri-miRNAs) to mature miRNAs.(104,135) Additionally, m(6)A also regulates”
• METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6‐methyladenosine‐dependent primary MicroRNA processing (2017, background): “Recently, Alarcon and colleagues demonstrated that m(6)A modification could mark primiRNAs for processing by recognizing DGCR8 in a manner dependent on METTL3/m(6)A, suggesting that altered METTL3/m(6)A might contribute to the aberrant expression of miRNAs in many biological processes, including can”
• Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018, background): “DGCR8 recognizes an N6-methyladenylated GGAC and other motifs within the primiRNA (28), while Drosha cleaves the pri-miRNA duplex at the base of the characteristic hairpin structure of pri-miRNA.”
• Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “, 2016), breast cancer cells (MDA-MB-231 cells) (Alarcon et al., 2015b), and acute myeloid leukemia cells (MOLM13 cells) (Barbieri et al.”
• SRAMP: prediction of mammalian N6-methyladenosine (m6A) sites based on sequence-derived features (2016, background): “F1 − score = 2 × TP 2 × TP + FP + FN (7)”
• RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation (2015, background): “Collectively, these studies suggest a potential regulatory network between the miRNA-based regulation and the m(6)A-dependent regulation as two main pathways that post-transcriptionally control gene expression (Alarcon et al. 2015; Berulava et al. 2015; Chen et al. 2015b).”