MicroRNA (miRNA) biogenesis

Stable Identifier
R-HSA-203927
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Pathway
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Homo sapiens
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Biogenesis of microRNAs (miRNAs) can be summarized in five steps (reviewed in Ketting 2011, Nowotny and Yang 2009, Kim et al. 2009, Chua et al. 2009, Hannon and He 2004):
1. Transcription. miRNA transcripts may come from autonomously transcribed genes, they may be contained in cotranscripts with other genes, or they may be located in introns of host genes. Most miRNAs are transcribed by RNA polymerase II, however a few miRNAs originate as RNA polymerase III cotranscripts with neighboring repetitive elements. The initial transcript, termed a primary microRNA (pri-miRNA), contains an imperfectly double-stranded region within a hairpin loop. Longer sequences extend from the 5' and 3' ends of the hairpin and may also contain double-stranded regions.
2. Cleavage by DROSHA. The 5' and 3' ends of the pri-miRNA are removed during endoribonucleolytic cleavage by the DROSHA nuclease in a complex with the RNA-binding protein DGCR8 (the Microprocessor complex). The cleavage product is a short hairpin of about 60 to 70 nt called the pre-microRNA (pre-miRNA).
3. Nuclear export by Exportin-5. The resulting pre-miRNA is bound by Exportin-5 in a complex with Ran and GTP. The complex translocates the pre-miRNA through the nuclear pore into the cytoplasm.
4. Cleavage by DICER1. Once in the cytoplasm the pre-miRNA is bound by the RISC loading complex which contains DICER1, an Argonaute protein and either TARBP2 or PRKRA. DICER1 cleaves the pre-miRNA to yield an imperfectly double-stranded miRNA of about 21 to 23 nucleotides. At this stage the double-stranded miRNA has protruding single-stranded 3' ends of 2-3 nt.
5. Incorporation into RNA-Induced Silencing Complex (RISC) and strand selection. The double-stranded miRNA is passed to a Argonaute protein contained in the RISC loading complex. One strand, the passenger strand, will be removed and degraded; the other strand, the guide strand, will be retained and will guide the Argonaute:miRNA complex (RISC) to target mRNAs.
The human genome encodes 4 Argonaute proteins (AGO1 (EIF2C1), AGO2 (EIF2C2), AGO3 (EIF2C3), AGO4 (EIF2C4)), however only AGO2 (EIF2C2) can cleave target mRNAs with perfect or nearly perfect complementarity to the guide miRNA. For complexes that contain AGO2, cleavage of the passenger strand of the double-stranded miRNA accompanies removal of the passenger strand. Complexes containing other Argonautes may use a helicase to remove the passenger strand but this is not fully known. The resulting miRNA-loaded AGO2 is predominantly located in complexes with TARBP2 or PRKRA at the cytosolic face of the rough endoplasmic reticulum. AGO2, TARBP2, and DICER1 are also observed in the nucleus.

Literature References
PubMed ID Title Journal Year
23511973 The rough endoplasmatic reticulum is a central nucleation site of siRNA-mediated RNA silencing

Stalder, L, Heusermann, W, Sokol, L, Trojer, D, Wirz, J, Hean, J, Fritzsche, A, Aeschimann, F, Pfanzagl, V, Basselet, P, Weiler, J, Hintersteiner, M, Morrissey, DV, Meisner-Kober, NC

EMBO J. 2013
24388755 RNAi factors are present and active in human cell nuclei

Gagnon, KT, Li, L, Chu, Y, Janowski, BA, Corey, DR

Cell Rep 2014
15944707 A microRNA polycistron as a potential human oncogene

He, L, Thomson, JM, Hemann, MT, Hernando-Monge, E, Mu, D, Goodson, S, Powers, S, Cordon-Cardo, C, Lowe, SW, Hannon, GJ, Hammond, SM

Nature 2005
19330724 MicroRNAs: biogenesis, function and applications

Chua, JH, Armugam, A, Jeyaseelan, K

Curr Opin Mol Ther 2009
8252621 The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14

Lee, RC, Feinbaum, RL, Ambros, V

Cell 1993
21755468 microRNA Biogenesis and Function : An overview

Ketting, RF

Adv Exp Med Biol 2011
19165215 Biogenesis of small RNAs in animals

Kim, VN, Han, J, Siomi, MC

Nat Rev Mol Cell Biol 2009
17057362 Intronic microRNA (miRNA)

Lin, SL, Miller, JD, Ying, SY

J Biomed Biotechnol 2006
15211354 MicroRNAs: small RNAs with a big role in gene regulation

Hannon, GJ, He, L

Nat Rev Genet 2004
15364901 Identification of mammalian microRNA host genes and transcription units

Rodriguez, A, Griffiths-Jones, S, Ashurst, JL, Bradley, A

Genome Res 2004
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