A Dicer-independent miRNA biogenesis pathway that requires Ago catalysis

By Sihem Cheloufi, C. D. dos Santos, M. Chong, Gregory J. Hannon. Nature, 2010

1,152 citations recorded by the source corpus.

The nucleolytic activity of animal Argonaute proteins is deeply conserved, despite its having no obvious role in microRNA-directed gene regulation. In mice, Ago2 (also known as Eif2c2) is uniquely required for viability, and only this family member retains catalytic competence. To investigate the evolutionary pressure to conserve Argonaute enzymatic activity, we engineered a mouse with catalytically inactive Ago2 alleles. Homozygous mutants died shortly after birth with an obvious anaemia. Examination of microRNAs and their potential targets revealed a loss of miR-451, a small RNA important for erythropoiesis. Though this microRNA is processed by Drosha (also known as Rnasen), its maturation does not require Dicer. Instead, the pre-miRNA becomes loaded into Ago and is cleaved by the Ago catalytic centre to generate an intermediate 3′ end, which is then further trimmed. Our findings link the conservation of Argonaute catalysis to a conserved mechanism of microRNA biogenesis that is important for vertebrate development.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a2318f5628b82af360003cc51ed39410be7ed060

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Citations in the corpus

Metazoan MicroRNAs (2018, background): “…by Dicer and instead directly enters Argonaute2 (Ago2), which cleaves the 3′ arm of the hairpin to generate a product that is further resected by the PARN exonuclease to produce the mature miRNA (Cheloufi et al., 2010; Cifuentes et al., 2010; Yang et al., 2010; Yoda et al., 2013) (Figure 3E).”
Human box C/D snoRNAs with miRNA like functions: expanding the range of regulatory RNAs (2010, background): “Processing of the human miR-451 resulted in overlapping and loop-spanning mature miRNAs in a presumably ago2 mediated and Dicer independent mechanism (55,56).”
Evolution and Functional Diversification of MIRNA Genes (2011, background): “Although loop-distal processing occurs first during miRNA maturation of most foldbacks in plants and animals, alternative primary processing events have been characterized (Okamura et al., 2007; Ruby et al., 2007; Addo-Quaye et al., 2009; Bologna et al., 2009; Cheloufi et al., 2010; Cifuentes et al.”
miRBase: annotating high confidence microRNAs using deep sequencing data (2013, background): “For example, the vertebrate microRNA mir451 has been shown to be processed by a Dicer-independent pathway (18).”
LincRNA-p21 suppresses target mRNA translation. (2012, background): “These interactions appeared to be functional, as MEFs deficient in Ago2, a necessary component of let-7/RISC (Cheloufi et al., 2010), displayed higher lincRNA-p21 levels (Figure S2D).”
Extracellular miRNAs: From Biomarkers to Mediators of Physiology and Disease (2019, background): “DICERindependent pathways of miRNA biogenesis have also been reported (Cheloufi et al., 2010), but their impact in miRNA synthesis is limited.”
MicroRNA in Control of Gene Expression: An Overview of Nuclear Functions (2016, background): “Mature agotrons are similar to pre-miRNAs (80–100 nt), and their biogenesis is independent of both Drosha and Dicer although they are ultimately associated and stabilized by Argonaute (AGO) proteins [14].”
MicroRNAs in human cancer. (2013, background): “Reductions in the amount of DICER1 resulting in impaired miRNA processing have also been shown to increase the rate of tumor formation in two different cancer mouse models, a K-RAS-driven lung cancer [88] and an Rb-driven retinoblastoma [89].”