Molecular Basis for Interaction of Let-7 MicroRNAs with Lin28

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Nov 15

PMID 22078496

Citations 224

Authors

Yunsun Nam

Casandra Chen

Richard I Gregory

James J Chou

Piotr Sliz

Affiliations

Soon will be listed here.

Abstract

MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate gene expression. Among these, members of the let-7 miRNA family control many cell-fate determination genes to influence pluripotency, differentiation, and transformation. Lin28 is a specific, posttranscriptional inhibitor of let-7 biogenesis. We report crystal structures of mouse Lin28 in complex with sequences from let-7d, let-7-f1, and let-7 g precursors. The two folded domains of Lin28 recognize two distinct regions of the RNA and are sufficient for inhibition of let-7 in vivo. We also show by NMR spectroscopy that the linker connecting the two folded domains is flexible, accommodating Lin28 binding to diverse let-7 family members. Protein-RNA complex formation imposes specific conformations on both components that could affect downstream recognition by other processing factors. Our data provide a molecular explanation for Lin28 specificity and a model for how it regulates let-7.

Citing Articles

Developing novel Lin28 inhibitors by computer aided drug design.

Matias-Barrios V, Radaeva M, Rosellinny G, Jia Q, Xie N, Villanueva M Cell Death Discov. 2025; 11(1):5.

PMID: 39800739 PMC: 11725581. DOI: 10.1038/s41420-024-02281-z.

The structural landscape of Microprocessor-mediated processing of pri-let-7 miRNAs.

Garg A, Shang R, Cvetanovic T, Lai E, Joshua-Tor L Mol Cell. 2024; 84(21):4175-4190.e6.

PMID: 39368465 PMC: 11560618. DOI: 10.1016/j.molcel.2024.09.008.

Nephron-Specific Overexpression Triggers Severe Inflammatory Response and Kidney Damage.

Futorian A, Armon L, Waldman Ben-Asher H, Shoval I, Hazut I, Munitz A Int J Biol Sci. 2024; 20(10):4044-4054.

PMID: 39113694 PMC: 11302891. DOI: 10.7150/ijbs.97434.

Poised PABP-RNA hubs implement signal-dependent mRNA decay in development.

Modic M, Kuret K, Steinhauser S, Faraway R, van Genderen E, Ruiz de Los Mozos I Nat Struct Mol Biol. 2024; 31(9):1439-1447.

PMID: 39054355 PMC: 11402784. DOI: 10.1038/s41594-024-01363-x.

Structural basis for activity switching in polymerases determining the fate of let-7 pre-miRNAs.

Yi G, Ye M, Carrique L, El-Sagheer A, Brown T, Norbury C Nat Struct Mol Biol. 2024; 31(9):1426-1438.

PMID: 39054354 PMC: 11402785. DOI: 10.1038/s41594-024-01357-9.

References

De Guzman R, Wu Z, Stalling C, Pappalardo L, Borer P, Summers M . Structure of the HIV-1 nucleocapsid protein bound to the SL3 psi-RNA recognition element. Science. 1998; 279(5349):384-8. DOI: 10.1126/science.279.5349.384. View

Michlewski G, Caceres J . Antagonistic role of hnRNP A1 and KSRP in the regulation of let-7a biogenesis. Nat Struct Mol Biol. 2010; 17(8):1011-8. PMC: 2923024. DOI: 10.1038/nsmb.1874. View

Zhang X, Zeng Y . The terminal loop region controls microRNA processing by Drosha and Dicer. Nucleic Acids Res. 2010; 38(21):7689-97. PMC: 2995066. DOI: 10.1093/nar/gkq645. View

Walker S, Avis J, Conn G . General plasmids for producing RNA in vitro transcripts with homogeneous ends. Nucleic Acids Res. 2003; 31(15):e82. PMC: 169970. DOI: 10.1093/nar/gng082. View

Zeng Y, Cullen B . Efficient processing of primary microRNA hairpins by Drosha requires flanking nonstructured RNA sequences. J Biol Chem. 2005; 280(30):27595-603. DOI: 10.1074/jbc.M504714200. View

Zhu H, Shah S, Shyh-Chang N, Shinoda G, Einhorn W, Viswanathan S . Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies. Nat Genet. 2010; 42(7):626-30. PMC: 3069638. DOI: 10.1038/ng.593. View

Ong K, Elks C, Li S, Zhao J, Luan J, Andersen L . Genetic variation in LIN28B is associated with the timing of puberty. Nat Genet. 2009; 41(6):729-33. PMC: 3000552. DOI: 10.1038/ng.382. View

Max K, Zeeb M, Bienert R, Balbach J, Heinemann U . T-rich DNA single strands bind to a preformed site on the bacterial cold shock protein Bs-CspB. J Mol Biol. 2006; 360(3):702-14. DOI: 10.1016/j.jmb.2006.05.044. View

Peng S, Maihle N, Huang Y . Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer. Oncogene. 2010; 29(14):2153-9. DOI: 10.1038/onc.2009.500. View

10.

Viswanathan S, Daley G . Lin28: A microRNA regulator with a macro role. Cell. 2010; 140(4):445-9. DOI: 10.1016/j.cell.2010.02.007. View

11.

Qiu C, Ma Y, Wang J, Peng S, Huang Y . Lin28-mediated post-transcriptional regulation of Oct4 expression in human embryonic stem cells. Nucleic Acids Res. 2009; 38(4):1240-8. PMC: 2831306. DOI: 10.1093/nar/gkp1071. View

12.

Zeng Y, Cullen B . Sequence requirements for micro RNA processing and function in human cells. RNA. 2003; 9(1):112-23. PMC: 1370375. DOI: 10.1261/rna.2780503. View

13.

Viswanathan S, Powers J, Einhorn W, Hoshida Y, Ng T, Toffanin S . Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet. 2009; 41(7):843-8. PMC: 2757943. DOI: 10.1038/ng.392. View

14.

Viswanathan S, Daley G, Gregory R . Selective blockade of microRNA processing by Lin28. Science. 2008; 320(5872):97-100. PMC: 3368499. DOI: 10.1126/science.1154040. View

15.

Lu L, Katsaros D, Shaverdashvili K, Qian B, Wu Y, de la Longrais I . Pluripotent factor lin-28 and its homologue lin-28b in epithelial ovarian cancer and their associations with disease outcomes and expression of let-7a and IGF-II. Eur J Cancer. 2009; 45(12):2212-8. DOI: 10.1016/j.ejca.2009.05.003. View

16.

Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C . let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007; 131(6):1109-23. DOI: 10.1016/j.cell.2007.10.054. View

17.

Kim V, Han J, Siomi M . Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol. 2009; 10(2):126-39. DOI: 10.1038/nrm2632. View

18.

Du Z, Lee J, Tjhen R, Stroud R, James T . Structural and biochemical insights into the dicing mechanism of mouse Dicer: a conserved lysine is critical for dsRNA cleavage. Proc Natl Acad Sci U S A. 2008; 105(7):2391-6. PMC: 2268147. DOI: 10.1073/pnas.0711506105. View

19.

Rybak A, Fuchs H, Smirnova L, Brandt C, Pohl E, Nitsch R . A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment. Nat Cell Biol. 2008; 10(8):987-93. DOI: 10.1038/ncb1759. View

20.

Iliopoulos D, Hirsch H, Struhl K . An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell. 2009; 139(4):693-706. PMC: 2783826. DOI: 10.1016/j.cell.2009.10.014. View