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How miRNA Structure of Animals Influences Their Biogenesis

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MicroRNAs are small noncoding RNAs that are involved in the post-transcriptional regulation of the gene expression in various organisms. This article reviews recent advances in understanding the role of the primary and secondary structures of animal miRNA precursors through the biogenesis stages and the miRNA maturation steps. Also, we describe the effects of genetic variability and heterogeneity of miRNA ends, which play an important role in epitranscriptomics as well as annotation errors in the miRNA databases.

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  1. 1

    Kutter, C. and Svoboda, P., miRNA, siRNA, piRNA: knowns of the unknown, RNA Biol., 2008, vol. 5, no. 4, pp. 181–188. https://doi.org/10.4161/rna.7227

  2. 2

    Lee, Y., Jeon, K., Lee, J.-T., et al., MicroRNA maturation: stepwise processing and subcellular localization, EMBO J., 2002, vol. 21, no. 17, pp. 4663–4670.

  3. 3

    O’Brien, J., Hayder, H., Zayed, Y., et al., Overview of microRNA biogenesis, mechanisms of actions, and circulation, Front. Endocrinol., 2018, vol. 9, no. 402, pp. 1–12. https://doi.org/10.3389/fendo.2018.00402

  4. 4

    Vidigal, J.A. and Ventura, A., The biological functions of miRNAs: lessons from in vivo studies, Trends Cell Biol., 2015, vol. 25, no. 3, pp. 137–147. https://doi.org/10.1016/j.tcb.2014.11.004

  5. 5

    Borchert, G.M., Lanier, W., and Davidson, B.L., RNA polymerase III transcribes human microRNAs, Nat. Struct. Mol. Biol., 2006, vol. 13, no. 12, pp. 1097–1101. https://doi.org/10.1038/nsmb1167

  6. 6

    Cai, X., Hagedorn, C.H., and Cullen, B.R., Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs, RNA, 2004, vol. 10, no. 12, pp. 1957–1966. https://doi.org/10.1261/rna.7135204

  7. 7

    Ballarino, M., Pagano, F., Girardi, E., et al., Coupled RNA processing and transcription of intergenic primary microRNAs, Mol. Cell. Biol., 2009, vol. 29, no. 20, pp. 5632–5638. https://doi.org/10.1128/MCB.00664-09

  8. 8

    Marco, A., Ninova, M., and Griffiths-Jones, S., Multiple products from microRNA transcripts, Biochem. Soc. Trans., 2013, vol. 41, no. 4, pp. 850–854. https://doi.org/10.1042/BST20130035

  9. 9

    Titov, I.I. and Vorozheykin, P.S., Analysis of miRNA duplication in the human genome and the role of transposon evolution in this process, Russ. J. Genet: Appl. Res., 2011, vol. 1, no. 4, pp. 308–314. https://doi.org/10.1134/S2079059711040083

  10. 10

    Chang, T.-C., Pertea, M., Lee, S., et al., Genome-wide annotation of microRNA primary transcript structures reveals novel regulatory mechanisms, Genome Res., 2015, vol. 25, no. 9, pp. 1401–1409. https://doi.org/10.1101/gr.193607.115

  11. 11

    Scott, H., Howarth, J., Lee, Y.B., et al., MiR-3120 is a mirror microRNA that targets heat shock cognate protein 70 and auxilin messenger RNAs and regulates clathrin vesicle uncoating, J. Biol. Chem., 2012, vol. 287, no. 18, pp. 14726–14733. https://doi.org/10.1074/jbc.M111.326041

  12. 12

    Abasi, M., Kohram, F., Fallah, P., et al., Differential maturation of miR-17~92 cluster members in human cancer cell lines, Appl. Biochem. Biotechnol., 2017, vol. 182, no. 4, pp. 1540–1547. https://doi.org/10.1007/s12010-017-2416-5

  13. 13

    Wang, Y., Luo, J., Zhang, H., et al., MicroRNAs in the same clusters evolve to coordinately regulate functionally related genes, Mol. Biol. Evol., 2016, vol. 33, no. 9, pp. 2232–2247. https://doi.org/10.1093/molbev/msw089

  14. 14

    Lataniotis, L., Albrecht, A., Kok, F.O., et al., CRISPR/Cas9 editing reveals novel mechanisms of clustered microRNA regulation and function, Sci. Rep., 2017, vol. 7, no. 8585, pp. 1–14. https://doi.org/10.1038/s41598-017-09268-0

  15. 15

    Tong, Z., Cui, Q., Wang, J., et al., TransmiR v2.0: an updated transcription factor-microRNA regulation database, Nucleic Acids Res., 2019, vol. 47, no. D1, pp. D253–D258. https://doi.org/10.1093/nar/gky1023

  16. 16

    Ben-Ami, O., Pencovich, N., Lotem, J., et al., A regulatory interplay between miR-27a and Runx1 during megakaryopoiesis, Proc. Natl. Acad. Sci. U.S.A., 2009, vol. 106, no. 1, pp. 238–243. https://doi.org/10.1073/pnas.0811466106

  17. 17

    Wang, Y., Liang, H., Zhou, G., et al., HIC1 and miR-23~27~24 clusters form a double-negative feedback loop in breast cancer, Cell Death Differ., 2017, vol. 24, no. 3, pp. 421–432. https://doi.org/10.1038/cdd.2016.136

  18. 18

    Shalgi, R., Lieber, D., Oren, M., et al., Global and local architecture of the mammalian microRNA–transcription factor regulatory network, PLoS Comput. Biol., 2007, vol. 3, no. 7, pp. 1291–1304. https://doi.org/10.1371/journal.pcbi.0030131

  19. 19

    Barros-Silva, D., Costa-Pinheiro, P., Duarte, H., et al., MicroRNA-27a-5p regulation by promoter methylation and MYC signaling in prostate carcinogenesis, Cell Death Dis., 2018, vol. 9, no. 167, pp. 1–15. https://doi.org/10.1038/s41419-017-0241-y

  20. 20

    Munoz-Tello, P., Rajappa, L., Coquille, S., et al., Polyuridylation in eukaryotes: a 3'-end modification regulating RNA life, BioMed Res. Int., 2015, vol. 2015, pp. 1–12. https://doi.org/10.1155/2015/968127

  21. 21

    Zhao, B.S., Roundtree, I.A., and He, C., Post-transcriptional gene regulation by mRNA modifications, Nat. Rev. Mol. Cell Biol., 2017, vol. 18, no. 1, pp. 31–42. https://doi.org/10.1038/nrm.2016.132

  22. 22

    Fernandez, N., Cordiner, R.A., Young, R.S., et al., Genetic variation and RNA structure regulate microRNA biogenesis, Nat. Commun., 2017, vol. 8, no. 15114, pp. 1–12. https://doi.org/10.1038/ncomms15114

  23. 23

    Nguyen, T.A., Jo, M.H., Choi, Y.-G., et al., Functional anatomy of the human microprocessor, Cell, 2015, vol. 161, no. 6, pp. 1374–1387. https://doi.org/10.1016/j.cell.2015.05.010

  24. 24

    Kwon, S.C., Nguyen, T.A., Choi, Y.-G., et al., Structure of human DROSHA, Cell, 2016, vol. 164, nos. 1–2, pp. 81–90. https://doi.org/10.1016/j.cell.2015.12.019

  25. 25

    Suzuki, H.I., Yamagata, K., Sugimoto, K., et al., Modulation of microRNA processing by p53, Nature, 2009, vol. 460, no. 7254, pp. 529–533. https://doi.org/10.1038/nature08199

  26. 26

    Connerty, P., Ahadi, A., and Hutvagner, G., RNA binding proteins in the miRNA pathway, Int. J. Mol. Sci., 2015, vol. 17, no. 31, pp. 1–16. https://doi.org/10.3390/ijms17010031

  27. 27

    Treiber, T., Treiber, N., Plessmann, U., et al., A compendium of RNA-binding proteins that regulate microRNA biogenesis, Mol. Cell, 2017, vol. 66, no. 2, pp. 270–284. https://doi.org/10.1016/j.molcel.2017.03.014

  28. 28

    Michlewski, G., Guil, S., Semple, C.A., et al., Posttranscriptional regulation of miRNAs harboring conserved terminal loops, Mol. Cell, 2008, vol. 32, no. 3, pp. 383–393. https://doi.org/10.1016/j.molcel.2008.10.013

  29. 29

    Jean-Philippe, J., Paz, S., and Caputi, M., hnRNP A1: the Swiss army knife of gene expression, Int. J. Mol. Sci., 2013, vol. 14, no. 9, pp. 18999–19024. https://doi.org/10.3390/ijms140918999

  30. 30

    Michlewski, G. and Cáceres, J.F. Antagonistic role of hnRNP A1 and KSRP in the regulation of let-7a biogenesis, Nat. Struct. Mol. Biol., 2010, vol. 17, no. 8, pp. 1011–1018. https://doi.org/10.1038/nsmb.1874

  31. 31

    Trabucchi, M., Briata, P., Garcia-Mayoral, M., et al., The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs, Nature, 2009, vol. 459, no. 7249, pp. 1010–1014. https://doi.org/10.1038/nature08025

  32. 32

    Kawahara, Y. and Mieda-Sato, A., TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes, Proc. Natl. Acad. Sci. U.S.A., 2012, vol. 109, no. 9, pp. 3347–3352. https://doi.org/10.1073/pnas.1112427109

  33. 33

    Wu, S.-L., Fu, X., Huang, J., et al., Genome-wide analysis of YB-1-RNA interactions reveals a novel role of YB-1 in miRNA processing in glioblastoma multiforme, Nucleic Acids Res., 2015, vol. 43, no. 17, pp. 8516–8528. https://doi.org/10.1093/nar/gkv779

  34. 34

    Nguyen, T.A., Park, J., Dang, T.L., et al., Microprocessor depends on hemin to recognize the apical loop of primary microRNA, Nucleic Acids Res., 2018, vol. 46, no. 11, pp. 5726–5736. https://doi.org/10.1093/nar/gky248

  35. 35

    Kim, K., Nguyen, T.D., Li, S., et al., SRSF3 recruits DROSHA to the basal junction of primary microRNAs, RNA, 2018, vol. 24, no. 7, pp. 892–898. https://doi.org/10.1261/rna.065862.118

  36. 36

    Viswanathan, S.R. and Daley, G.Q., Lin28: a microRNA regulator with a macro role, Cell, 2010, vol. 140, no. 4, pp. 445–449. https://doi.org/10.1016/j.cell.2010.02.007

  37. 37

    Davis, B.N., Hilyard, A.C., Nguyen, P.H., et al., Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha, Mol. Cell, 2010, vol. 39, no. 3, pp. 373–384. https://doi.org/10.1016/j.molcel.2010.07.011

  38. 38

    Kawai, S. and Amano, A., BRCA1 regulates microRNA biogenesis via the DROSHA microprocessor complex, J. Cell Biol., 2012, vol. 197, no. 2, pp. 201–208. https://doi.org/10.1083/jcb.201110008

  39. 39

    Wu, H., Sun, S., Tu, K., et al., A splicing-independent function of SF2/ASF in microRNA processing, Mol. Cell, 2010, vol. 38, no. 1, pp. 67–77. https://doi.org/10.1016/j.molcel.2010.02.021

  40. 40

    Ha, M. and Kim, V.N., Regulation of microRNA biogenesis, Nat. Rev. Mol. Cell Biol., 2014, vol. 15, no. 8, pp. 509–524. https://doi.org/10.1038/nrm3838

  41. 41

    Auyeung, V.C., Ulitsky, I., McGeary, S.E., et al., Beyond secondary structure: primary-sequence determinants license pri-miRNA hairpins for processing, Cell, 2013, vol. 152, no. 4, pp. 844–858. https://doi.org/10.1016/j.cell.2013.01.031

  42. 42

    Bartel, D.P., Metazoan microRNAs, Cell, 2018, vol. 173, no. 1, pp. 20–51. https://doi.org/10.1016/j.cell.2018.03.006

  43. 43

    Fromm, B., Domanska, D., Hackenberg, M., et al., MirGeneDB2.0: the curated microRNA Gene Database, 2018. https://doi.org/10.1101/258749

  44. 44

    Tang, R., Li, L., Zhu, D., et al., Mouse miRNA-709 directly regulates miRNA-15a/16-1 biogenesis at the posttranscriptional level in the nucleus: evidence for a microRNA hierarchy system, Cell Res., 2012, vol. 22, no. 3, pp. 504–515. https://doi.org/10.1038/cr.2011.137

  45. 45

    Zisoulis, D.G., Kai, Z.S., Chang, R.K., et al., Autoregulation of microRNA biogenesis by let-7 and Argonaute, Nature, 2012, vol. 486, no. 7404, pp. 541–544. https://doi.org/10.1038/nature11134

  46. 46

    Sundaram, G.M., Common, J.E.A., Gopal, F.E., et al., ‘See-saw’ expression of microRNA-198 and FSTL1 from a single transcript in wound healing, Nature, 2013, vol. 495, no. 7439, pp. 103–106. https://doi.org/10.1038/nature11890

  47. 47

    Han, J., Pedersen, J.S., Kwon, S.C., et al., Posttranscriptional crossregulation between Drosha and DGCR8, Cell, 2009, vol. 136, no. 1, pp. 75–84. https://doi.org/10.1016/j.cell.2008.10.053

  48. 48

    Frixa, T., Sacconi, A., Cioce, M., et al., MicroRNA-128-3p-mediated depletion of Drosha promotes lung cancer cell migration, Carcinogenesis, 2018, vol. 39, no. 2, pp. 293–304. https://doi.org/10.1093/carcin/bgx134

  49. 49

    Yi, R., Qin, Y., Macara, I.G., et al., Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs, Genes Dev., 2003, vol. 17, no. 24, pp. 3011–3016. https://doi.org/10.1101/gad.1158803

  50. 50

    Büssing, I., Yang, J.-S., Lai, E.C., et al., The nuclear export receptor XPO-1 supports primary miRNA processing in C. elegans and Drosophila,EMBO J., 2010, vol. 29, no. 11, pp. 1830–1839. https://doi.org/10.1038/emboj.2010.82

  51. 51

    Xie, M., Li, M., Vilborg, A., et al., Mammalian 5'-capped microRNA precursors that generate a single microRNA, Cell, 2013, vol. 155, no. 7, pp. 1568–1580. https://doi.org/10.1016/j.cell.2013.11.027

  52. 52

    Zeng, Y., Structural requirements for pre-microRNA binding and nuclear export by Exportin 5, Nucleic Acids Res., 2004, vol. 32, no. 16, pp. 4776–4785. https://doi.org/10.1093/nar/gkh824

  53. 53

    Okada, C., Yamashita, E., Lee, S.J., et al., A high-resolution structure of the pre-microRNA nuclear export machinery, Science, 2009, vol. 326, no. 5957, pp. 1275–1279. https://doi.org/10.1126/science.1178705

  54. 54

    Bennasser, Y., Chable-Bessia, C., Triboulet, R., et al., Competition for XPO5 binding between Dicer mRNA, pre-miRNA and viral RNA regulates human Dicer levels, Nat. Struct. Mol. Biol., 2011, vol. 18, no. 3, pp. 323–327. https://doi.org/10.1038/nsmb.1987

  55. 55

    Melo, S.A., Moutinho, C., Ropero, S., et al., A genetic defect in exportin-5 traps precursor microRNAs in the nucleus of cancer cells, Cancer Cell, 2010, vol. 18, no. 4, pp. 303–315. https://doi.org/10.1016/j.ccr.2010.09.007

  56. 56

    Singh, C.P., Singh, J., and Nagaraju, J., A baculovirus-encoded microRNA (miRNA) suppresses its host miRNA biogenesis by regulating the Exportin-5 cofactor Ran, J. Virol., 2012, vol. 86, no. 15, pp. 7867–7879. https://doi.org/10.1128/JVI.00064-12

  57. 57

    MacRae, I.J., Zhou, K., Doudna, J.A., Structural determinants of RNA recognition and cleavage by Dicer, Nat. Struct. Mol. Biol., 2007, vol. 14, no. 10, pp. 934–940. https://doi.org/10.1038/nsmb1293

  58. 58

    Lau, P.-W., Guiley, K.Z., De, N., et al., The molecular architecture of human Dicer, Nat. Struct. Mol. Biol., 2012, vol. 19, no. 4, pp. 436–440. https://doi.org/10.1038/nsmb.2268

  59. 59

    MacRae, I.J., Structural basis for double-stranded RNA processing by Dicer, Science, 2006, vol. 311, no. 5758, pp. 195–198. https://doi.org/10.1126/science.1121638

  60. 60

    MacRae, I.J., Li, F., Zhou, K., et al., Structure of Dicer and mechanistic implications for RNAi, Cold Spring Harbor Symp. Quant. Biol., 2006, vol. 71, pp. 73–80. https://doi.org/10.1101/sqb.2006.71.042

  61. 61

    Park, J.-E., Heo, I., Tian, Y., et al., Dicer recognizes the 5' end of RNA for efficient and accurate processing, Nature, 2011, vol. 475, no. 7355, pp. 201–205. https://doi.org/10.1038/nature10198

  62. 62

    Thornton, J.E., Chang, H.-M., Piskounova, E., et al., Lin28-mediated control of let-7 microRNA expression by alternative TUTases Zcchc11 (TUT4) and Zcchc6 (TUT7), RNA, 2012, vol. 18, no. 10, pp. 1875–1885. https://doi.org/10.1261/rna.034538.112

  63. 63

    Newman, M.A., Thomson, J.M., and Hammond, S.M., Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing, RNA, 2008, vol. 14, no. 8, pp. 1539–1549. https://doi.org/10.1261/rna.1155108

  64. 64

    Bortolamiol-Becet, D., Hu, F., Jee, D., et al., Selective suppression of the splicing-mediated microRNA pathway by the terminal uridyltransferase Tailor, Mol. Cell, 2015, vol. 59, no. 2, pp. 217–228. https://doi.org/10.1016/j.molcel.2015.05.034

  65. 65

    Starega-Roslan, J., Witkos, T., Galka-Marciniak, P., et al., Sequence features of Drosha and Dicer cleavage sites affect the complexity of isomiRs, Int. J. Mol. Sci., 2015, vol. 16, no. 12, pp. 8110–8127. https://doi.org/10.3390/ijms16048110

  66. 66

    Heo, I., Ha, M., Lim, J., et al., Mono-uridylation of pre-microRNA as a key step in the biogenesis of group II let-7 microRNAs, Cell, 2012, vol. 151, no. 3, pp. 521–532. https://doi.org/10.1016/j.cell.2012.09.022

  67. 67

    Rau, F., Freyermuth, F., Fugier, C., et al., Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy, Nat. Struct. Mol. Biol., 2011, vol. 18, no. 7, pp. 840–845. https://doi.org/10.1038/nsmb.2067

  68. 68

    Chen, Y., Zubovic, L., Yang, F., et al., Rbfox proteins regulate microRNA biogenesis by sequence-specific binding to their precursors and target downstream Dicer, Nucleic Acids Res., 2016, vol. 44, no. 9, pp. 4381–4395. https://doi.org/10.1093/nar/gkw177

  69. 69

    Hellwig, S. and Bass, B.L., A starvation-induced noncoding RNA modulates expression of Dicer-regulated genes, Proc. Natl. Acad. Sci. U.S.A., 2008, vol. 105, no. 35, pp. 12897–12902. https://doi.org/10.1073/pnas.0805118105

  70. 70

    Iizasa, H., Wulff, B.-E., Alla, N.R., et al., Editing of Epstein—Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency, J. Biol. Chem., 2010, vol. 285, no. 43, pp. 33358–33370. https://doi.org/10.1074/jbc.M110.138362

  71. 71

    Gu, S., Jin, L., Zhang, Y., et al., The loop position of shRNAs and pre-miRNAs is critical for the accuracy of Dicer processing in vivo, Cell, 2012, vol. 151, no. 4, pp. 900–911. https://doi.org/10.1016/j.cell.2012.09.042

  72. 72

    Okamura, K. and Nakanishi, K., Argonaute Proteins, New York: Springer-Verlag, 2018. https://doi.org/10.1007/978-1-4939-7339-2

  73. 73

    Pinhal, D., Bovolenta, L.A., Moxon, S., et al., Genome-wide microRNA screening in Nile tilapia reveals pervasive isomiRs’ transcription, sex-biased arm switching and increasing complexity of expression throughout development, Sci. Rep., 2018, vol. 8, no. 8248, pp. 1–18. https://doi.org/10.1038/s41598-018-26607-x

  74. 74

    Suzuki, H.I., Katsura, A., Yasuda, T., et al., Small-RNA asymmetry is directly driven by mammalian Argonautes, Nat. Struct. Mol. Biol., 2015, vol. 22, no. 7, pp. 512–521. https://doi.org/10.1038/nsmb.3050

  75. 75

    Wright, D.J., Rice, J.L., Yanker, D.M., et al., Nearest neighbor parameters for inosine—uridine pairs in RNA duplexes, Biochemistry, 2007, vol. 46, no. 15, pp. 4625–4634. https://doi.org/10.1021/bi0616910

  76. 76

    Li, L., Song, Y., Shi, X., et al., The landscape of miRNA editing in animals and its impact on miRNA biogenesis and targeting, Genome Res., 2018, vol. 28, no. 1, pp. 132–143. https://doi.org/10.1101/gr.224386.117

  77. 77

    Berezikov, E., Evolution of microRNA diversity and regulation in animals, Nat. Rev. Genet., 2011, vol. 12, no. 12, pp. 846–860. https://doi.org/10.1038/nrg3079

  78. 78

    Hutvagner, G. and Simard, M.J., Argonaute proteins: key players in RNA silencing, Nat. Rev. Mol. Cell Biol., 2008, vol. 9, no. 1, pp. 22–32. https://doi.org/10.1038/nrm2321

  79. 79

    Ghildiyal, M., Xu, J., Seitz, H., et al., Sorting of Drosophila small silencing RNAs partitions microRNA* strands into the RNA interference pathway, RNA, 2010, vol. 16, no. 1, pp. 43–56. https://doi.org/10.1261/rna.1972910

  80. 80

    Ponomarenko, M.P., Suslov, V.V., Ponomarenko, P.M., et al., Abundances of microRNAs in human cells can be estimated as a function of the abundances of YRHB and RHHK tetranucleotides in these microRNAs as an ill-posed inverse problem solution, Front. Genet., 2013, vol. 4, pp. 1–13. https://doi.org/10.3389/fgene.2013.00122

  81. 81

    Okamura, K., Liu, N., and Lai, E.C., Distinct mechanisms for microRNA strand selection by Drosophila Argonautes, Mol. Cell, 2009, vol. 36, no. 3, pp. 431–444. https://doi.org/10.1016/j.molcel.2009.09.027

  82. 82

    Shin, C., Cleavage of the star strand facilitates assembly of some microRNAs into Ago2-containing silencing complexes in mammals, Cell, 2008, no. 26, pp. 308–313.

  83. 83

    Curtis, H.J., Sibley, C.R., and Wood, M.J.A., Mirtrons, an emerging class of atypical miRNA, Wiley Interdiscip. Rev.: RNA, 2012, vol. 3, no. 5, pp. 617–632. https://doi.org/10.1002/wrna.1122

  84. 84

    Ladewig, E., Okamura, K., Flynt, A.S., et al., Discovery of hundreds of mirtrons in mouse and human small RNA data, Genome Res., 2012, vol. 22, no. 9, pp. 1634–1645. https://doi.org/10.1101/gr.133553.111

  85. 85

    Wen, J., Ladewig, E., Shenker, S., Analysis of nearly one thousand mammalian mirtrons reveals novel features of Dicer substrates, PLoS Comput. Biol., 2015, vol. 11, no. 9, pp. 1–29. https://doi.org/10.1371/journal.pcbi.1004441

  86. 86

    Yang, L., Splicing noncoding RNAs from the inside out: splicing noncoding RNAs from the inside out, Wiley Interdiscip. Rev.: RNA, 2015, vol. 6, no. 6, pp. 651–660. https://doi.org/10.1002/wrna.1307

  87. 87

    Titov, I.I. and Vorozheykin, P.S., Comparing miRNA structure of mirtrons and non-mirtrons, BMC Genomics, 2018, vol. 19, no. S3, pp. 92–102. https://doi.org/10.1186/s12864-018-4473-8

  88. 88

    Berezikov, E., Liu, N., Flynt, A.S., et al., Evolutionary flux of canonical microRNAs and mirtrons in Drosophila,Nat. Genet., 2010, vol. 42, no. 1, pp. 6–9. https://doi.org/10.1038/ng0110-6

  89. 89

    Havens, M.A., Reich, A.A., Duelli, D.M., et al., Biogenesis of mammalian microRNAs by a non-canonical processing pathway, Nucleic Acids Res., 2012, vol. 40, no. 10, pp. 4626–4640. https://doi.org/10.1093/nar/gks026

  90. 90

    Abdelfattah, A.M., Park, C., and Choi, M.Y., Update on non-canonical microRNAs, Biomol. Concepts, 2014, vol. 5, no. 4, pp. 275–287. https://doi.org/10.1515/bmc-2014-0012

  91. 91

    Stagsted, L.V.W., Daugaard, I., and Hansen, T.B., The agotrons: gene regulators or Argonaute protectors? BioEssays, 2017, vol. 39, no. 4, pp. 1–6. https://doi.org/10.1002/bies.201600239

  92. 92

    Cheloufi, S., Dos Santos, C.O., Chong, M.M.W., et al., A dicer-independent miRNA biogenesis pathway that requires Ago catalysis, Nature, 2010, vol. 465, no. 7298, pp. 584–589. https://doi.org/10.1038/nature09092

  93. 93

    Cifuentes, D., Xue, H., Taylor, D.W., et al., A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity, Science, 2010, vol. 328, no. 5986, pp. 1694–1698. https://doi.org/10.1126/science.1190809

  94. 94

    Yoda, M., Cifuentes, D., Izumi, N., et al., Poly(A)-specific ribonuclease mediates 3'-end trimming of Argonaute2-cleaved precursor microRNAs, Cell Rep., 2013, vol. 5, no. 3, pp. 715–726. https://doi.org/10.1016/j.celrep.2013.09.029

  95. 95

    Yang, J.-S., Maurin, T., and Lai, E.C., Functional parameters of Dicer-independent microRNA biogenesis, RNA, 2012, vol. 18, no. 5, pp. 945–957. https://doi.org/10.1261/rna.032938.112

  96. 96

    Wheeler, B.M., Heimberg, A.M., Moy, V.N., et al., The deep evolution of metazoan microRNAs, Evol. Dev., 2009, vol. 11, no. 1, pp. 50–68. https://doi.org/10.1111/j.1525-142X.2008.00302.x

  97. 97

    Kolchanov, N.A., Titov, I.I., Vlassova, I.E., et al., Chemical and computer probing of RNA structure, Progr. Nucleic Acid Res. Mol. Biol., 1996, vol. 53, pp. 131–196. https://doi.org/10.1016/S0079-6603(08)60144-0

  98. 98

    Slezak-Prochazka, I., Durmus, S., Kroesen, B.J., et al., MicroRNAs, macrocontrol: regulation of miRNA processing, RNA, 2010, vol. 16, no. 6, pp. 1087–1095. https://doi.org/10.1261/rna.1804410

  99. 99

    Gong, J., Tong, Y., Zhang, H.-M., et al., Genome-wide identification of SNPs in microRNA genes and the SNP effects on microRNA target binding and biogenesis, Hum. Mutat., 2012, vol. 33, no. 1, pp. 254–263. https://doi.org/10.1002/humu.21641

  100. 100

    Sun, G., Yan, J., Noltner, K., et al., SNPs in human miRNA genes affect biogenesis and function, RNA, 2009, vol. 15, no. 9, pp. 1640–1651. https://doi.org/10.1261/rna.1560209

  101. 101

    Hill, D.A., Ivanovich, J., Priest, J.R., et al., DICER1 mutations in familial pleuropulmonary blastoma, Science, 2009, vol. 325, no. 5943, pp. 965–965. https://doi.org/10.1126/science.1174334

  102. 102

    Nishikura, K., A-to-I editing of coding and non-coding RNAs by ADARs, Nat. Rev. Mol. Cell Biol., 2016, vol. 17, no. 2, pp. 83–96. https://doi.org/10.1038/nrm.2015.4

  103. 103

    Tomaselli, S., Bonamassa, B., Alisi, A., et al., ADAR enzyme and miRNA story: a nucleotide that can make the difference, Int. J. Mol. Sci., 2013, vol. 14, no. 11, pp. 22796–22816. https://doi.org/10.3390/ijms141122796

  104. 104

    Kawahara, Y., Zinshteyn, B., Sethupathy, P., et al., Redirection of silencing targets by adenosine-to-inosine editing of miRNAs, Science, 2007, vol. 315, no. 5815, pp. 1137–1140. https://doi.org/10.1126/science.1138050

  105. 105

    Kawahara, Y., Zinshteyn, B., Chendrimada, T.P., et al., RNA editing of the microRNA-151 precursor blocks cleavage by the Dicer–TRBP complex, EMBO Rep., 2007, vol. 8, no. 8, pp. 763–769. https://doi.org/10.1038/sj.embor.7401011

  106. 106

    Zhang, F., Lu, Y., Yan, S., et al., SPRINT: an SNP-free toolkit for identifying RNA editing sites, Bioinformatics, 2017, vol. 33, no. 22, pp. 3538–3548. https://doi.org/10.1093/bioinformatics/btx473

  107. 107

    Neilsen, C.T., Goodall, G.J., and Bracken, C.P., IsomiRs—the overlooked repertoire in the dynamic microRNAome, Trends Genet., 2012, vol. 28, no. 11, pp. 544–549. https://doi.org/10.1016/j.tig.2012.07.005

  108. 108

    Starega-Roslan, J., Galka-Marciniak, P., and Krzyzosiak, W.J., Nucleotide sequence of miRNA precursor contributes to cleavage site selection by Dicer, Nucleic Acids Res., 2015, vol. 43, no. 22, pp. 10939–10951. https://doi.org/10.1093/nar/gkv968

  109. 109

    Li, S. and Patel, D.J., Drosha and Dicer: slicers cut from the same cloth, Cell Res., 2016, vol. 26, no. 5, pp. 511–512. https://doi.org/10.1038/cr.2016.19

  110. 110

    Ma, M., Yin, Z., Zhong, H., et al., Analysis of the expression, function, and evolution of miR-27 isoforms and their responses in metabolic processes, Genomics, 2018. https://doi.org/10.1016/j.ygeno.2018.08.004

  111. 111

    Yu, F., Pillman, K.A., Neilsen, C.T., et al., Naturally existing isoforms of miR-222 have distinct functions, Nucleic Acids Res., 2017, vol. 45, no. 19, pp. 11371–11385. https://doi.org/10.1093/nar/gkx788

  112. 112

    Han, B.W., Hung, J.-H., Weng, Z., et al., The 3'-to-5' exoribonuclease nibbler shapes the 3' ends of microRNAs bound to Drosophila Argonaute1, Curr. Biol., 2011, vol. 21, no. 22, pp. 1878–1887. https://doi.org/10.1016/j.cub.2011.09.034

  113. 113

    Liu, N., Abe, M., Sabin, L.R., et al., The exoribonuclease nibbler controls 3' end processing of microRNAs in Drosophila,Curr. Biol., 2011, vol. 21, no. 22, pp. 1888–1893. https://doi.org/10.1016/j.cub.2011.10.006

  114. 114

    Norbury, C.J., Cytoplasmic RNA: a case of the tail wagging the dog, Nat. Rev. Mol. Cell Biol., 2013, vol. 14, no. 10, pp. 643–653. https://doi.org/10.1038/nrm3645

  115. 115

    Tan, G.C. and Dibb, N., IsomiRs have functional importance, Malays J. Pathol., 2015, vol. 37, no. 2, pp. 73–81.

  116. 116

    McCall, M.N., Kim, M.-S., Adil, M., et al., Toward the human cellular microRNAome, Genome Res., 2017, vol. 27, no. 10, pp. 1769–1781. https://doi.org/10.1101/gr.222067.117

  117. 117

    Ludwig, N., Becker, M., Schumann, T., et al., Bias in recent miRBase annotations potentially associated with RNA quality issues, Sci. Rep., 2017, vol. 7, no. 5162, pp. 1–11. https://doi.org/10.1038/s41598-017-05070-0

  118. 118

    Fromm, B., Billipp, T., Peck, L.E., et al., A uniform system for the annotation of vertebrate microRNA genes and the evolution of the human microRNAome, Annu. Rev. Genet., 2015, vol. 49, no. 1, pp. 213–242. https://doi.org/10.1146/annurev-genet-120213-092023

  119. 119

    Hou, D., He, F., Ma, L., et al., The potential atheroprotective role of plant MIR156a as a repressor of monocyte recruitment on inflamed human endothelial cells, J. Nutr. Biochem., 2018, vol. 57, pp. 197–205. https://doi.org/10.1016/j.jnutbio.2018.03.026

  120. 120

    Fromm, B., Kang, W., Rovira, C., et al., Plant microRNAs in human sera are likely contaminants, J. Nutr. Biochem., 2018. https://doi.org/10.1016/j.jnutbio.2018.07.019

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This work was supported by the state budget project 0324-2019-0040.

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Correspondence to P. S. Vorozheykin.

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Vorozheykin, P.S., Titov, I.I. How miRNA Structure of Animals Influences Their Biogenesis. Russ J Genet 56, 17–29 (2020). https://doi.org/10.1134/S1022795420010135

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  • miRNA
  • pre-miRNA
  • secondary structure
  • biogenesis
  • mirtron
  • single nucleotide polymorphism
  • mutation
  • epigenetics