The Biogenesis and Regulation of Animal MicroRNAs

Overview

Journal Nat Rev Mol Cell Biol

Specialties Cell Biology
Molecular Biology

Date 2024 Dec 20

PMID 39702526

Authors

Haedong Kim

Young-Yoon Lee

V Narry Kim

Affiliations

Soon will be listed here.

Abstract

MicroRNAs (miRNAs) are small, yet profoundly influential, non-coding RNAs that base-pair with mRNAs to induce RNA silencing. Although the basic principles of miRNA biogenesis and function have been established, recent breakthroughs have yielded important new insights into the molecular mechanisms of miRNA biogenesis. In this Review, we discuss the metazoan miRNA biogenesis pathway step-by-step, focusing on the key biogenesis machinery, including the Drosha-DGCR8 complex (Microprocessor), exportin-5, Dicer and Argonaute. We also highlight newly identified cis-acting elements and their impact on miRNA maturation, informed by advanced high-throughput and structural studies, and discuss recently discovered mechanisms of clustered miRNA processing, target recognition and target-directed miRNA decay (TDMD). Lastly, we explore multiple regulatory layers of miRNA biogenesis, mediated by RNA-protein interactions, miRNA tailing (uridylation or adenylation) and RNA modifications.

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References

Lee R, Feinbaum R, Ambros V . The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993; 75(5):843-54. DOI: 10.1016/0092-8674(93)90529-y. View

Wightman B, Ha I, Ruvkun G . Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell. 1993; 75(5):855-62. DOI: 10.1016/0092-8674(93)90530-4. View

Bartel D . Metazoan MicroRNAs. Cell. 2018; 173(1):20-51. PMC: 6091663. DOI: 10.1016/j.cell.2018.03.006. View

Gebert L, MacRae I . Regulation of microRNA function in animals. Nat Rev Mol Cell Biol. 2018; 20(1):21-37. PMC: 6546304. DOI: 10.1038/s41580-018-0045-7. View

Iwakawa H, Tomari Y . Life of RISC: Formation, action, and degradation of RNA-induced silencing complex. Mol Cell. 2021; 82(1):30-43. DOI: 10.1016/j.molcel.2021.11.026. View

Friedman R, Farh K, Burge C, Bartel D . Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2008; 19(1):92-105. PMC: 2612969. DOI: 10.1101/gr.082701.108. View

Lee Y, Kim M, Han J, Yeom K, Lee S, Baek S . MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 2004; 23(20):4051-60. PMC: 524334. DOI: 10.1038/sj.emboj.7600385. View

Cai X, Hagedorn C, Cullen B . Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA. 2004; 10(12):1957-66. PMC: 1370684. DOI: 10.1261/rna.7135204. View

Hutvagner G, McLachlan J, Pasquinelli A, Balint E, Tuschl T, Zamore P . A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science. 2001; 293(5531):834-8. DOI: 10.1126/science.1062961. View

10.

Ketting R, Fischer S, Bernstein E, Sijen T, Hannon G, Plasterk R . Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev. 2001; 15(20):2654-9. PMC: 312808. DOI: 10.1101/gad.927801. View

11.

Bernstein E, Caudy A, Hammond S, Hannon G . Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature. 2001; 409(6818):363-6. DOI: 10.1038/35053110. View

12.

Grishok A, Pasquinelli A, Conte D, Li N, Parrish S, Ha I . Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell. 2001; 106(1):23-34. DOI: 10.1016/s0092-8674(01)00431-7. View

13.

Knight S, Bass B . A role for the RNase III enzyme DCR-1 in RNA interference and germ line development in Caenorhabditis elegans. Science. 2001; 293(5538):2269-71. PMC: 1855227. DOI: 10.1126/science.1062039. View

14.

Lee Y, Jeon K, Lee J, Kim S, Kim V . MicroRNA maturation: stepwise processing and subcellular localization. EMBO J. 2002; 21(17):4663-70. PMC: 126204. DOI: 10.1093/emboj/cdf476. View

15.

Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J . The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003; 425(6956):415-9. DOI: 10.1038/nature01957. View

16.

Han J, Lee Y, Yeom K, Kim Y, Jin H, Kim V . The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev. 2004; 18(24):3016-27. PMC: 535913. DOI: 10.1101/gad.1262504. View

17.

Gregory R, Yan K, Amuthan G, Chendrimada T, Doratotaj B, Cooch N . The Microprocessor complex mediates the genesis of microRNAs. Nature. 2004; 432(7014):235-40. DOI: 10.1038/nature03120. View

18.

Denli A, Tops B, Plasterk R, Ketting R, Hannon G . Processing of primary microRNAs by the Microprocessor complex. Nature. 2004; 432(7014):231-5. DOI: 10.1038/nature03049. View

19.

Landthaler M, Yalcin A, Tuschl T . The human DiGeorge syndrome critical region gene 8 and Its D. melanogaster homolog are required for miRNA biogenesis. Curr Biol. 2004; 14(23):2162-7. DOI: 10.1016/j.cub.2004.11.001. View

20.

Tabara H, SARKISSIAN M, KELLY W, Fleenor J, Grishok A, Timmons L . The rde-1 gene, RNA interference, and transposon silencing in C. elegans. Cell. 1999; 99(2):123-32. DOI: 10.1016/s0092-8674(00)81644-x. View