An RNA-binding Protein, Lin28, Recognizes and Remodels G-quartets in the MicroRNAs (miRNAs) and mRNAs It Regulates

O’Day, Elizabeth; Le, Minh Tn; Imai, Shunsuke; Tan, Shen Mynn; Kirchner, Rory; Arthanari, Haribabu; Hofmann, Oliver; Wagner, Gerhard; Lieberman, Judy

doi:10.1074/jbc.m115.665521

Cited by 33 publications

(29 citation statements)

References 76 publications

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“…Identifying GQs as targets for regulatory proteins. NMM was instrumental in demonstrating that GQs can be recognized by regulatory proteins such as Lin28 [80] and p53 [81]. NMM was identified as the first small molecule inhibitor of Lin28, a conserved RNA-binding protein overexpressed in many cancers and linked to poor prognoses.…”

Section: Using Nmm To Study Gq Dna In Biological Contextsmentioning

confidence: 99%

N-methyl mesoporphyrin IX as a highly selective light-up probe for G-quadruplex DNA

Yett

Lin

Beseiso

et al. 2019

J. Porphyrins Phthalocyanines

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[Formula: see text]-methyl mesoporphyrin IX (NMM) is a water-soluble, non-symmetric porphyrin with excellent optical properties and unparalleled selectivity for G-quadruplex (GQ) DNA. G-quadruplexes are non-canonical DNA structures formed by guanine-rich sequences. They are implicated in genomic stability, longevity, and cancer. The ability of NMM to selectively recognize GQ structures makes it a valuable scaffold for designing novel GQ binders. In this review, we survey the literature describing the GQ-binding properties of NMM as well as its wide utility in chemistry and biology. We start with the discovery of the GQ-binding properties of NMM and the development of NMM-binding aptamers. We then discuss the optical properties of NMM, focusing on the light-switch effect — high fluorescence of NMM induced upon its binding to GQ DNA. Additionally, we examine the affinity and selectivity of NMM for GQs, as well as its ability to stabilize GQ structures and favor parallel GQ conformations. Furthermore, a portion of the review is dedicated to the applications of NMM-GQ complexes as biosensors for heavy metals, small molecules ([Formula: see text] ATP and pesticides), DNA, and proteins. Finally and importantly, we discuss the utility of NMM as a probe to investigate the roles of GQs in biological processes.

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Section: Using Nmm To Study Gq Dna In Biological Contextsmentioning

confidence: 99%

N-methyl mesoporphyrin IX as a highly selective light-up probe for G-quadruplex DNA

Yett

Lin

Beseiso

et al. 2019

J. Porphyrins Phthalocyanines

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“…Finally, given that RBPs contribute directly or indirectly to remodel these structures in mRNAs and that G4s colocalize with miRNAs (126,127), do the alteration in RBPs expression deregulate miRNA-mediated gene expression mechanisms?…”

Section: Perspectivementioning

confidence: 99%

RNA G-quadruplexes: emerging mechanisms in disease

2016

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RNA G-quadruplexes (G4s) are formed by G-rich RNA sequences in protein-coding (mRNA) and non-coding (ncRNA) transcripts that fold into a four-stranded conformation. Experimental studies and bioinformatic predictions support the view that these structures are involved in different cellular functions associated to both DNA processes (telomere elongation, recombination and transcription) and RNA post-transcriptional mechanisms (including pre-mRNA processing, mRNA turnover, targeting and translation). An increasing number of different diseases have been associated with the inappropriate regulation of RNA G4s exemplifying the potential importance of these structures on human health. Here, we review the different molecular mechanisms underlying the link between RNA G4s and human diseases by proposing several overlapping models of deregulation emerging from recent research, including (i) sequestration of RNA-binding proteins, (ii) aberrant expression or localization of RNA G4-binding proteins, (iii) repeat associated non-AUG (RAN) translation, (iv) mRNA translational blockade and (v) disabling of protein–RNA G4 complexes. This review also provides a comprehensive survey of the functional RNA G4 and their mechanisms of action. Finally, we highlight future directions for research aimed at improving our understanding on RNA G4-mediated regulatory mechanisms linked to diseases.

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“…The RNA-binding protein Lin28b blocks let-7 biogenesis (16,17), and the Lin28b 39-untranslated region contains several highly conserved let-7 miRNA binding sites (Supplementary Fig. 4).…”

Section: Tnf-a and Pdgf Regulate Let-7 Expression Via Lin28bmentioning

confidence: 99%

“…Mature let-7 family members contain identical sequences and, as a result, act to suppress the expression of a common set of target mRNAs (15). let-7 family members have a distinct expression pattern in animal development, largely regulated by the RNA-binding protein Lin28, with let-7 expression repressed in the embryonic stages of development (16)(17)(18). The let-7/lin28 axis has been implicated as a master regulator of cell proliferation and differentiation, with reduced let-7 miRNA expression reported in epithelial-to-mesenchymal transition and enhanced cell migration/invasion (19,20).…”

mentioning

confidence: 99%

Protective Effect of let-7 miRNA Family in Regulating Inflammation in Diabetes-Associated Atherosclerosis

et al. 2017

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The let-7 miRNA family plays a key role in modulating inflammatory responses. Vascular smooth muscle cell (SMC) proliferation and endothelial cell (EC) dysfunction are critical in the pathogenesis of atherosclerosis, including in the setting of diabetes. Here we report that let-7 levels are decreased in diabetic human carotid plaques and in a model of diabetes-associated atherosclerosis, the diabetic ApoE mouse. In vitro platelet-derived growth factor (PDGF)- and tumor necrosis factor-α (TNF-α)-induced vascular SMC and EC activation was associated with reduced let-7 miRNA expression via Lin28b, a negative regulator of let-7 biogenesis. Ectopic overexpression of let-7 in SMCs inhibited inflammatory responses including proliferation, migration, monocyte adhesion, and nuclear factor-κB activation. The therapeutic potential of restoring let-7 levels using a let-7 mimic was tested: in vitro in SMCs using an endogenous anti-inflammatory lipid (lipoxin A), ex vivo in murine aortas, and in vivo via tail vein injection in a 24-h murine model. Furthermore, we delivered let-7 mimic to human carotid plaque ex vivo and observed significant changes to the secretome in response to let-7 therapy. Restoration of let-7 expression could provide a new target for an anti-inflammatory approach in diabetic vascular disease.

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An RNA-binding Protein, Lin28, Recognizes and Remodels G-quartets in the MicroRNAs (miRNAs) and mRNAs It Regulates

Cited by 33 publications

References 76 publications

N-methyl mesoporphyrin IX as a highly selective light-up probe for G-quadruplex DNA

N-methyl mesoporphyrin IX as a highly selective light-up probe for G-quadruplex DNA

RNA G-quadruplexes: emerging mechanisms in disease

Protective Effect of let-7 miRNA Family in Regulating Inflammation in Diabetes-Associated Atherosclerosis

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