4x8w

Structural highlights

Function

LOQS_DROME Double-stranded RNA-binding protein which can function in gene silencing by acting with Dcr-1 to enhance its ATP-independent processing of a specific subset of precursor micro-RNAs (pre-miRNAs) to mature miRNAs (PubMed:19635780, PubMed:26769856, PubMed:27184838). Some reports found it was able to enhance the efficiency of pre-miRNA processing by Dcr-1, and can shift the cleavage site of Dcr-1 altering the length of the mature miRNAs produced by Dcr-1 alone (PubMed:17320391, PubMed:23063653, PubMed:29373753). However, in contrast to isoform PB, it is not necessary or sufficient for enhancing miRNA biogenesis, and is not required for development or female germline stem cell (GSC) maintenance (PubMed:17320391, PubMed:23063653). Another report also found that it decreases binding of Dcr-1 to the miRNA substrate let-7 (PubMed:17928574).^{[1] [2] [3] [4] [5] [6] [7]} Double-stranded RNA-binding protein which functions in gene silencing by acting with Dcr-1 to enhance its ATP-independent processing of a specific subset of precursor micro-RNAs (pre-miRNAs) to mature miRNAs (PubMed:15918769, PubMed:15985611, PubMed:17666393, PubMed:17928574, PubMed:19635780, PubMed:26769856, PubMed:27184838, PubMed:36182693). Function is essential for development and female germline stem cell (GSC) maintenance (PubMed:15985611, PubMed:17320391, PubMed:23063653). Functions in miRNA-mediated gene silencing by enhancing the binding affinity and specific pre-miRNA processing activity of Dcr-1, and as part of the loqs-PB-Dcr-1 complex, is involved in substrate discrimination, correctly positioning the pre-miRNA in the Dcr-1 catalytic center for cleavage, and miRNA loading into the Argonaute 1 (Ago1)-containing RNA-induced silencing complex (miRISC) (PubMed:15918769, PubMed:17666393, PubMed:17928574, PubMed:23063653, PubMed:27184838, PubMed:36182693). Increases the binding affinity of Dcr-1 to pre-miRNAs, thereby increasing dicing efficiency and broadening the range of substrates that can be processed by the dicer (PubMed:17928574, PubMed:23063653, PubMed:27184838, PubMed:36182693). It may also confer the substrate specificity of Dcr-1 towards pre-miRNAs, as in its absence Dcr-1 displays siRNA-generating activity towards long dsRNA substrates (PubMed:15918769). It can also shift the cleavage site of Dcr-1 for a small number of pre-miRNAs, changing the length of the mature miRNAs produced by Dcr-1 alone (PubMed:23063653, PubMed:29373753). Increases the range of pre-miRNAs that can be processed by Dcr-1, by enhancing the dicing of suboptimal hairpin substrates including ones with mismatches at the dicing site (PubMed:27184838, PubMed:29373753). This function may also promote the generation of novel miRNA genes as it appears to have an important role in processing evolutionarily young miRNA genes, suggesting that it may also enhance dicing of substrates that have not acquired hairpin features required for efficient miRNA processing (PubMed:27184838). As newly emerged miRNAs can have deleterious or beneficial effects on fitness, this function is likely part of a regulatory system that prevents excessive emergence of active miRNA genes and thus keeps them within an optimal range (PubMed:27184838). Also forms a RISC loading complex (miRLC) with Dcr-1 to mediate Ago1-loading of mature miRNAs into the RNA-induced silencing complex (miRISC) (PubMed:15918769, PubMed:36182693). In female ovaries, required for Dcr-1 to generate the twenty-three nucleotide isomiR variant of miR-307a which is able to repress its targets Gk2 and tara (PubMed:23063653).^{[8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]} Double-stranded RNA-binding protein which has an essential role in gene silencing (RNAi) by acting with Dcr-2 to enhance its ATP-dependent processing of a subset of endogenous (endo) and exogenous (exo) dsRNAs into short interfering RNAs (siRNAs) (PubMed:19635780, PubMed:19644447, PubMed:21245036, PubMed:23063653, PubMed:25891075, PubMed:27184838, PubMed:28874570, PubMed:29040648, PubMed:29550490, PubMed:34590626). Functions in RNAi by increasing the initial binding affinity of Dcr-2 to certain dsRNA substrates, and in the absence of r2d2, may also function in siRNA loading into the Argonaute 2 (AGO2)-containing RNA-induced silencing complex (siRISC) and guide strand selection for target silencing by the siRISC (PubMed:19635780, PubMed:19644447, PubMed:21245036, PubMed:29550490). Promotes Dcr-2 cleavage of a subset of dsRNAs, including endo-dsRNAs derived from convergent transcription, inverted repeats and transposons (PubMed:19635780, PubMed:19644447, PubMed:21245036, PubMed:23063653, PubMed:29550490). Also enables Dcr-2 to produce hairpin-derived endo-siRNAs in the presence of cellular inhibitory inorganic phosphate, likely by increasing the binding affinity of the enzyme to the hairpin dsRNAs allowing the dsRNA to displace phosphate bound to Dcr-2 (PubMed:29550490). According to many reports, the cleavage reaction mode of Dcr-2 changes according to the termini of the dsRNA substrate, with the enzyme displaying a preference for processing blunt termini (BLT), likely non-self dsRNAs, over dsRNAs with 2 nucleotides 3' overhanging (3'ovr) termini, which are typically the structure of endo-dsRNAs (PubMed:25891075, PubMed:29550490, PubMed:34590626). According to many reports, interaction with Loqs-PD modifies the molecular recognition mechanisms of Dcr-2 towards sub-optimal 3'ovr dsRNA substrates and thus enables the dicer to cleave endo-dsRNA templates with diverse termini (PubMed:25891075, PubMed:29550490). However, according to another report, the mode of cleavage reaction is not affected by the presence or absence of loqs-PD (PubMed:34590626). In the absence of r2d2, may also form an alternative RISC loading complex (siRLC) with Dcr-2 to mediate AGO2-loading of endo- and exo-siRNAs into the RNA-induced silencing complex (siRISC) (PubMed:21245036, PubMed:29040648). Many reports suggest that loqs-PD and r2d2 function independently with dcr-2 in distinct siRNA pathways, and may even compete for binding to the enzyme (PubMed:21245036, PubMed:29040648). Loaded siRNAs serve as a guide to direct the siRISC to complementary RNAs to degrade them or prevent their translation (PubMed:29040648). The siRLC plays an important role in the ATP-dependent asymmetry sensing of the duplex, and is therefore also responsible for the selection of the strand that ultimately acts as the guide siRNA for the siRISC (PubMed:29040648). Thermodynamically asymmetric endo-siRNAs can be pre-oriented in the siRLC by the Loqs-PD and DCr-2 complex, which preferentially binds to the most thermodynamically stable strand prior to loading into the siRISC (PubMed:29040648). Appears to be involved in promoting double-strand breaks (DSBs) following exposure to a low-dose/dose-rate (LDR) of ionizing radiation (PubMed:36057690).^{[19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29]}

References

1. ↑ Park JK, Liu X, Strauss TJ, McKearin DM, Liu Q. The miRNA pathway intrinsically controls self-renewal of Drosophila germline stem cells. Curr Biol. 2007 Mar 20;17(6):533-8. PMID:17320391 doi:10.1016/j.cub.2007.01.060
2. ↑ Liu X, Park JK, Jiang F, Liu Y, McKearin D, Liu Q. Dicer-1, but not Loquacious, is critical for assembly of miRNA-induced silencing complexes. RNA. 2007 Dec;13(12):2324-9. PMID:17928574 doi:10.1261/rna.723707
3. ↑ Zhou R, Czech B, Brennecke J, Sachidanandam R, Wohlschlegel JA, Perrimon N, Hannon GJ. Processing of Drosophila endo-siRNAs depends on a specific Loquacious isoform. RNA. 2009 Oct;15(10):1886-95. PMID:19635780 doi:10.1261/rna.1611309
4. ↑ Fukunaga R, Han BW, Hung JH, Xu J, Weng Z, Zamore PD. Dicer partner proteins tune the length of mature miRNAs in flies and mammals. Cell. 2012 Oct 26;151(3):533-46. PMID:23063653 doi:10.1016/j.cell.2012.09.027
5. ↑ Jakob L, Treiber T, Treiber N, Gust A, Kramm K, Hansen K, Stotz M, Wankerl L, Herzog F, Hannus S, Grohmann D, Meister G. Structural and functional insights into the fly microRNA biogenesis factor Loquacious. RNA. 2016 Mar;22(3):383-96. PMID:26769856 doi:10.1261/rna.055426.115
6. ↑ Lim MY, Ng AW, Chou Y, Lim TP, Simcox A, Tucker-Kellogg G, Okamura K. The Drosophila Dicer-1 Partner Loquacious Enhances miRNA Processing from Hairpins with Unstable Structures at the Dicing Site. Cell Rep. 2016 May 24;15(8):1795-808. PMID:27184838 doi:10.1016/j.celrep.2016.04.059
7. ↑ Zhu L, Kandasamy SK, Fukunaga R. Dicer partner protein tunes the length of miRNAs using base-mismatch in the pre-miRNA stem. Nucleic Acids Res. 2018 Apr 20;46(7):3726-3741. PMID:29373753 doi:10.1093/nar/gky043
8. ↑ Saito K, Ishizuka A, Siomi H, Siomi MC. Processing of pre-microRNAs by the Dicer-1-Loquacious complex in Drosophila cells. PLoS Biol. 2005 Jul;3(7):e235. PMID:15918769 doi:10.1371/journal.pbio.0030235
9. ↑ Jiang F, Ye X, Liu X, Fincher L, McKearin D, Liu Q. Dicer-1 and R3D1-L catalyze microRNA maturation in Drosophila. Genes Dev. 2005 Jul 15;19(14):1674-9. PMID:15985611 doi:10.1101/gad.1334005
10. ↑ Park JK, Liu X, Strauss TJ, McKearin DM, Liu Q. The miRNA pathway intrinsically controls self-renewal of Drosophila germline stem cells. Curr Biol. 2007 Mar 20;17(6):533-8. PMID:17320391 doi:10.1016/j.cub.2007.01.060
11. ↑ Ye X, Paroo Z, Liu Q. Functional anatomy of the Drosophila microRNA-generating enzyme. J Biol Chem. 2007 Sep 28;282(39):28373-28378. PMID:17666393 doi:10.1074/jbc.M705208200
12. ↑ Liu X, Park JK, Jiang F, Liu Y, McKearin D, Liu Q. Dicer-1, but not Loquacious, is critical for assembly of miRNA-induced silencing complexes. RNA. 2007 Dec;13(12):2324-9. PMID:17928574 doi:10.1261/rna.723707
13. ↑ Zhou R, Czech B, Brennecke J, Sachidanandam R, Wohlschlegel JA, Perrimon N, Hannon GJ. Processing of Drosophila endo-siRNAs depends on a specific Loquacious isoform. RNA. 2009 Oct;15(10):1886-95. PMID:19635780 doi:10.1261/rna.1611309
14. ↑ Fukunaga R, Han BW, Hung JH, Xu J, Weng Z, Zamore PD. Dicer partner proteins tune the length of mature miRNAs in flies and mammals. Cell. 2012 Oct 26;151(3):533-46. PMID:23063653 doi:10.1016/j.cell.2012.09.027
15. ↑ Jakob L, Treiber T, Treiber N, Gust A, Kramm K, Hansen K, Stotz M, Wankerl L, Herzog F, Hannus S, Grohmann D, Meister G. Structural and functional insights into the fly microRNA biogenesis factor Loquacious. RNA. 2016 Mar;22(3):383-96. PMID:26769856 doi:10.1261/rna.055426.115
16. ↑ Lim MY, Ng AW, Chou Y, Lim TP, Simcox A, Tucker-Kellogg G, Okamura K. The Drosophila Dicer-1 Partner Loquacious Enhances miRNA Processing from Hairpins with Unstable Structures at the Dicing Site. Cell Rep. 2016 May 24;15(8):1795-808. PMID:27184838 doi:10.1016/j.celrep.2016.04.059
17. ↑ Zhu L, Kandasamy SK, Fukunaga R. Dicer partner protein tunes the length of miRNAs using base-mismatch in the pre-miRNA stem. Nucleic Acids Res. 2018 Apr 20;46(7):3726-3741. PMID:29373753 doi:10.1093/nar/gky043
18. ↑ Jouravleva K, Golovenko D, Demo G, Dutcher RC, Hall TMT, Zamore PD, Korostelev AA. Structural basis of microRNA biogenesis by Dicer-1 and its partner protein Loqs-PB. Mol Cell. 2022 Nov 3;82(21):4049-4063.e6. doi: 10.1016/j.molcel.2022.09.002. Epub, 2022 Sep 30. PMID:36182693 doi:http://dx.doi.org/10.1016/j.molcel.2022.09.002
19. ↑ Zhou R, Czech B, Brennecke J, Sachidanandam R, Wohlschlegel JA, Perrimon N, Hannon GJ. Processing of Drosophila endo-siRNAs depends on a specific Loquacious isoform. RNA. 2009 Oct;15(10):1886-95. PMID:19635780 doi:10.1261/rna.1611309
20. ↑ Hartig JV, Esslinger S, Böttcher R, Saito K, Förstemann K. Endo-siRNAs depend on a new isoform of loquacious and target artificially introduced, high-copy sequences. EMBO J. 2009 Oct 7;28(19):2932-44. PMID:19644447 doi:10.1038/emboj.2009.220
21. ↑ Hartig JV, Förstemann K. Loqs-PD and R2D2 define independent pathways for RISC generation in Drosophila. Nucleic Acids Res. 2011 May;39(9):3836-51. PMID:21245036 doi:10.1093/nar/gkq1324
22. ↑ Fukunaga R, Han BW, Hung JH, Xu J, Weng Z, Zamore PD. Dicer partner proteins tune the length of mature miRNAs in flies and mammals. Cell. 2012 Oct 26;151(3):533-46. PMID:23063653 doi:10.1016/j.cell.2012.09.027
23. ↑ Sinha NK, Trettin KD, Aruscavage PJ, Bass BL. Drosophila dicer-2 cleavage is mediated by helicase states that are modulated by Loquacious-PD. Mol Cell. 2015 May 7;58(3):406-17. PMID:25891075 doi:10.1016/j.molcel.2015.03.012
24. ↑ Lim MY, Ng AW, Chou Y, Lim TP, Simcox A, Tucker-Kellogg G, Okamura K. The Drosophila Dicer-1 Partner Loquacious Enhances miRNA Processing from Hairpins with Unstable Structures at the Dicing Site. Cell Rep. 2016 May 24;15(8):1795-808. PMID:27184838 doi:10.1016/j.celrep.2016.04.059
25. ↑ Trettin KD, Sinha NK, Eckert DM, Apple SE, Bass BL. Loquacious-PD facilitates Drosophila Dicer-2 cleavage through interactions with the helicase domain and dsRNA. Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):E7939-E7948. PMID:28874570 doi:10.1073/pnas.1707063114
26. ↑ Tants JN, Fesser S, Kern T, Stehle R, Geerlof A, Wunderlich C, Juen M, Hartlmuller C, Bottcher R, Kunzelmann S, Lange O, Kreutz C, Forstemann K, Sattler M. Molecular basis for asymmetry sensing of siRNAs by the Drosophila Loqs-PD/Dcr-2 complex in RNA interference. Nucleic Acids Res. 2017 Oct 13. doi: 10.1093/nar/gkx886. PMID:29040648 doi:http://dx.doi.org/10.1093/nar/gkx886
27. ↑ Fukunaga R. Loquacious-PD removes phosphate inhibition of Dicer-2 processing of hairpin RNAs into siRNAs. Biochem Biophys Res Commun. 2018 Apr 15;498(4):1022-1027. PMID:29550490 doi:10.1016/j.bbrc.2018.03.108
28. ↑ Jonely M, Singh RK, Donelick HM, Bass BL, Noriega R. Loquacious-PD regulates the terminus-dependent molecular recognition of Dicer-2 toward double-stranded RNA. Chem Commun (Camb). 2021 Oct 19;57(83):10879-10882. PMID:34590626 doi:10.1039/d1cc03843e
29. ↑ Porrazzo A, Cipressa F, De Gregorio A, De Pittà C, Sales G, Ciapponi L, Morciano P, Esposito G, Tabocchini MA, Cenci G. Low dose rate γ-irradiation protects fruit fly chromosomes from double strand breaks and telomere fusions by reducing the esi-RNA biogenesis factor Loquacious. Commun Biol. 2022 Sep 3;5(1):905. PMID:36057690 doi:10.1038/s42003-022-03885-w