Lin28a uses distinct mechanisms of binding to RNA and affects miRNA levels positively and negatively

Nowak, Jakub Stanislaw; Hóbor, Fruzsina; Velasco, Angela Downie Ruiz; Choudhury, Nila Roy; Heikel, Gregory; Kerr, Alastair; Ramos, Andrés; Michlewski, Gracjan

doi:10.1261/rna.059196.116

Cited by 31 publications

(30 citation statements)

References 67 publications

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“…Importantly, the difference of the two subclasses in LIN28 binding affinity is clearly reflected in the complementary interactome capture assay (Treiber et al, 2017). This proposed model explains why isolated CSD does not bind, or binds only weakly, to human let-7a-1 (Nowak et al, 2017) and Xtr-pre-let-7f (Mayr et al, 2012), which do not have the GAU motif, but binds efficiently to let-7d, let-7f-1, and let-7g, which contain the GAU (Wang et al, 2017). Coincidentally, the crystal structure of LIN28 and let-7 was obtained for three Class I let-7 family members, but not any Class II family members (Nam et al, 2011).…”

Section: Discussionmentioning

confidence: 91%

LIN28 selectively modulates a subclass of let-7 microRNAs

Ustianenko

Chiu

Weyn-Vanhentenryck

et al. 2017

Preprint

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LIN28 is a bipartite RNA-binding protein that post-transcriptionally inhibits let-7 microRNAs to regulate development and influence disease states. However, the mechanisms of let-7 suppression remains poorly understood, because LIN28 recognition depends on coordinated targeting by both the zinc knuckle domain (ZKD) -which binds a GGAG-like element in the precursor-and the cold shock domain (CSD), whose binding sites have not been systematically characterized. By leveraging single-nucleotide-resolution mapping of LIN28 binding sites in vivo, we determined that the CSD recognizes a (U)GAU motif. This motif partitions the let-7 family into Class I precursors with both CSD and ZKD binding sites and Class II precursors with ZKD but no CSD binding sites. LIN28 in vivo recognition-and subsequent 3ʹ uridylation and degradation-of Class I precursors is more efficient, leading to their stronger suppression in LIN28-activated cells and cancers. Thus, CSD binding sites amplify the effects of the LIN28 activation with potential implication in development and cancer.

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Section: Discussionmentioning

confidence: 91%

LIN28 selectively modulates a subclass of let-7 microRNAs

Ustianenko

Chiu

Weyn-Vanhentenryck

et al. 2017

Preprint

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“…The difference of the two subclasses in LIN28 binding affinity and the contribution of CSD to specific binding were also validated using in vitro binding assays including RNA-mediated interactome capture and EMSA together with mutagenesis analyses. This proposed model explains why isolated CSD does not bind, or binds only weakly, to human let-7a-1 (Nowak et al, 2017) and Xtr-pre-let-7f (Mayr et al, 2012), which do not have the GAU motif, but binds efficiently to let-7d, let-7f-1, and let-7g, which contain the GAU (Wang et al, 2017). Coincidentally, the crystal structure of LIN28 and let-7 was obtained for three CSD + let-7 family members, but not any CSD − family members (Nam et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

LIN28 Selectively Modulates a Subclass of Let-7 MicroRNAs

et al. 2018

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Summary LIN28 is a bipartite RNA-binding protein that post-transcriptionally inhibits the biogenesis of let-7 microRNAs to regulate development and influence disease states. However, the mechanisms of let-7 suppression remains poorly understood, because LIN28 recognition depends on coordinated targeting by both the zinc knuckle domain (ZKD)—which binds a GGAG-like element in the precursor—and the cold shock domain (CSD), whose binding sites have not been systematically characterized. By leveraging single-nucleotide-resolution mapping of LIN28 binding sites in vivo, we determined that the CSD recognizes a (U)GAU motif. This motif partitions the let-7 microRNAs into two subclasses, precursors with both CSD and ZKD binding sites (CSD+) and precursors with ZKD but no CSD binding sites (CSD−). LIN28 in vivo recognition—and subsequent 3ʹ uridylation and degradation—of CSD+ precursors is more efficient, leading to their stronger suppression in LIN28-activated cells and cancers. Thus, CSD binding sites amplify the regulatory effects of LIN28.

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“…This inhibitory effect of let-7 production is important to block miRNA-mediated differentiation in stem cells. LIN28A also inhibits the biogenesis of the neuro-specific miRNA-9 during neuronal differentiation of mouse cells (Nowak et al 2014(Nowak et al , 2017, albeit using an uridylation-independent mechanism.…”

Section: Role Of Rbps In the Regulation Of Mirna Biogenesismentioning

confidence: 99%

Post-transcriptional control of miRNA biogenesis

Michlewski

Cáceres

2018

RNA

Self Cite

435

330

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MicroRNAs (miRNAs) are important regulators of gene expression that bind complementary target mRNAs and repress their expression. Precursor miRNA molecules undergo nuclear and cytoplasmic processing events, carried out by the endoribonucleases DROSHA and DICER, respectively, to produce mature miRNAs that are loaded onto the RISC (RNA-induced silencing complex) to exert their biological function. Regulation of mature miRNA levels is critical in development, differentiation, and disease, as demonstrated by multiple levels of control during their biogenesis cascade. Here, we will focus on post-transcriptional mechanisms and will discuss the impact of cis-acting sequences in precursor miRNAs, as well as transacting factors that bind to these precursors and influence their processing. In particular, we will highlight the role of general RNA-binding proteins (RBPs) as factors that control the processing of specific miRNAs, revealing a complex layer of regulation in miRNA production and function.

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Lin28a uses distinct mechanisms of binding to RNA and affects miRNA levels positively and negatively

Cited by 31 publications

References 67 publications

LIN28 selectively modulates a subclass of let-7 microRNAs

LIN28 selectively modulates a subclass of let-7 microRNAs

LIN28 Selectively Modulates a Subclass of Let-7 MicroRNAs

Post-transcriptional control of miRNA biogenesis

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