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Structural and functional basis of mammalian microRNA biogenesis by Dicer.
<div class='caption-title'>DExD/HEL1 domain of Dicer but not its ATPase activity is essential for miRNA homeostasis and normal mouse development</div>
<div class='caption-title'>HEL1 restricts processing of mirtrons and 3p passenger strand loading</div>
Zapletal D, Taborska E, Pasulka J, Malik R, Kubicek K, Zanova M, Much C, Sebesta M, Buccheri V, Horvat F, Jenickova I, Prochazkova M, Prochazka J, Pinkas M, Novacek J, Joseph DF, Sedlacek R, Bernecky C, O'Carroll D, Stefl R, Svoboda P
OpenAccess logo Mol Cell 82 4064-4079.e13 (2022)
Related entries: 7yym, 7yyn, 7yz4, 7zpi, 7zpk

Cited: 20 times
EuropePMC logo PMID: 36332606

Abstract

MicroRNA (miRNA) and RNA interference (RNAi) pathways rely on small RNAs produced by Dicer endonucleases. Mammalian Dicer primarily supports the essential gene-regulating miRNA pathway, but how it is specifically adapted to miRNA biogenesis is unknown. We show that the adaptation entails a unique structural role of Dicer's DExD/H helicase domain. Although mice tolerate loss of its putative ATPase function, the complete absence of the domain is lethal because it assures high-fidelity miRNA biogenesis. Structures of murine Dicer•-miRNA precursor complexes revealed that the DExD/H domain has a helicase-unrelated structural function. It locks Dicer in a closed state, which facilitates miRNA precursor selection. Transition to a cleavage-competent open state is stimulated by Dicer-binding protein TARBP2. Absence of the DExD/H domain or its mutations unlocks the closed state, reduces substrate selectivity, and activates RNAi. Thus, the DExD/H domain structurally contributes to mammalian miRNA biogenesis and underlies mechanistical partitioning of miRNA and RNAi pathways.

Reviews citing this publication (8)

  1. microRNAs in action: biogenesis, function and regulation. Shang R, Lee S, Senavirathne G, Lai EC. Nat Rev Genet 24 816-833 (2023)
  2. Network Regulation of microRNA Biogenesis and Target Interaction. Komatsu S, Kitai H, Suzuki HI. Cells 12 306 (2023)
  3. Dicer structure and function: conserved and evolving features. Zapletal D, Kubicek K, Svoboda P, Stefl R. EMBO Rep 24 e57215 (2023)
  4. Emerging Role of MicroRNA-30c in Neurological Disorders. Kumar M, Li G. Int J Mol Sci 24 37 (2022)
  5. Profiling miRNAs of Teleost Fish in Responses to Environmental Stress: A Review. Cao Q, Zhang H, Li T, He L, Zong J, Shan H, Huang L, Zhang Y, Liu H, Jiang J. Biology (Basel) 12 388 (2023)
  6. Themes and variations on piRNA-guided transposon control. Loubalova Z, Konstantinidou P, Haase AD. Mob DNA 14 10 (2023)
  7. Recent progress in miRNA biogenesis and decay. Bofill-De Ros X, Vang Ørom UA. RNA Biol 21 1-8 (2024)
  8. Superfamily II helicases: the potential therapeutic target for cardiovascular diseases. Fang T, Wang X, Huangfu N. Front Cardiovasc Med 10 1309491 (2023)

Articles citing this publication (12)

  1. Structure of the human DICER-pre-miRNA complex in a dicing state. Lee YY, Lee H, Kim H, Kim VN, Roh SH. Nature 615 331-338 (2023)
  2. Structural basis of microRNA biogenesis by Dicer-1 and its partner protein Loqs-PB. Jouravleva K, Golovenko D, Demo G, Dutcher RC, Hall TMT, Zamore PD, Korostelev AA. Mol Cell 82 4049-4063.e6 (2022)
  3. Ancestral protein reconstruction reveals evolutionary events governing variation in Dicer helicase function. Aderounmu AM, Aruscavage PJ, Kolaczkowski B, Bass BL. Elife 12 e85120 (2023)
  4. DICER ribonuclease removes harmful R-loops. Camino LP, Dutta A, Barroso S, Pérez-Calero C, Katz JN, García-Rubio M, Sung P, Gómez-González B, Aguilera A. Mol Cell 83 3707-3719.e5 (2023)
  5. Comment MicroRNA uses a gym to get fit for cuts by Dicer enzyme. Meister G. Nature 615 218-219 (2023)
  6. Promiscuous splicing-derived hairpins are dominant substrates of tailing-mediated defense of miRNA biogenesis in mammals. Lee S, Jee D, Srivastava S, Yang A, Ramidi A, Shang R, Bortolamiol-Becet D, Pfeffer S, Gu S, Wen J, Lai EC. Cell Rep 42 112111 (2023)
  7. DICER1 platform domain missense variants inhibit miRNA biogenesis and lead to tumor susceptibility. Pelletier D, Chong AL, Wu M, Witkowski L, Albert S, Sabbaghian N, Fabian MR, Foulkes WD. NAR Cancer 5 zcad030 (2023)
  8. EZH2-H3K27me3-mediated silencing of mir-139-5p inhibits cellular senescence in hepatocellular carcinoma by activating TOP2A. Wang K, Jiang X, Jiang Y, Liu J, Du Y, Zhang Z, Li Y, Zhao X, Li J, Zhang R. J Exp Clin Cancer Res 42 320 (2023)
  9. Functional canonical RNAi in mice expressing a truncated Dicer isoform and long dsRNA. Buccheri V, Pasulka J, Malik R, Loubalova Z, Taborska E, Horvat F, Roos Kulmann MI, Jenickova I, Prochazka J, Sedlacek R, Svoboda P. EMBO Rep 25 2896-2913 (2024)
  10. Substrate promiscuity of Dicer toward precursors of the let-7 family and their 3'-end modifications. Dadhwal G, Samy H, Bouvette J, El-Azzouzi F, Dagenais P, Legault P. Cell Mol Life Sci 81 53 (2024)
  11. The helicase domain of human Dicer prevents RNAi-independent activation of antiviral and inflammatory pathways. Baldaccini M, Gaucherand L, Chane-Woon-Ming B, Messmer M, Gucciardi F, Pfeffer S. EMBO J 43 806-835 (2024)
  12. Two-motif model illuminates DICER cleavage preferences. Le CT, Nguyen TD, Nguyen TA. Nucleic Acids Res 52 1860-1877 (2024)


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