Vimentin binds to G-quadruplex repeats found at telomeres and gene promoters

Ceschi, Silvia; Berselli, Michele; Giantin, Mery; Toppo, Stefano; Spolaore, Barbara; Sissi, Claudia

doi:10.1101/2021.05.25.444966

Cited by 3 publications

(2 citation statements)

References 55 publications

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“…22,23 Indeed, a very recent study reports that the intermediate filament protein Vimentin binds with nanomolar affinity to those G-rich sequences that form at least two adjacent G4 units. 82 Continued development of the ISB approach for higherorder G4 studies requires integration of additional biophysical and structural tools. Our preliminary efforts indicate that cryoelectron microscopy is one such tool that can be used, with very promising initial results.…”

Section: ■ Perspectivementioning

confidence: 99%

G-quadruplex DNA: A Longer Story

2022

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Conspectus G-quadruplexes (G4s) are distinctive four-stranded DNA or RNA structures found within cells that are thought to play functional roles in gene regulation and transcription, translation, recombination, and DNA damage/repair. While G4 structures can be uni-, bi-, or tetramolecular with respect to strands, folded unimolecular conformations are most significant in vivo. Unimolecular G4 can potentially form in sequences with runs of guanines interspersed with what will become loops in the folded structure: 5′G x L y G x L y G x L y G x , where x is typically 2–4 and y is highly variable. Such sequences are highly conserved and specifically located in genomes. In the folded structure, guanines from each run combine to form planar tetrads with four hydrogen-bonded guanine bases; these tetrads stack on one another to produce four strand segments aligned in specific parallel or antiparallel orientations, connected by the loop sequences. Three types of loops (lateral, diagonal, or “propeller”) have been identified. The stacked tetrads form a central cavity that features strong coordination sites for monovalent cations that stabilize the G4 structure, with potassium or sodium preferred. A single monomeric G4 typically forms from a sequence containing roughly 20–30 nucleotides. Such short sequences have been the primary focus of X-ray crystallographic or NMR studies that have produced high-resolution structures of a variety of monomeric G4 conformations. These structures are often used as the basis for drug design efforts to modulate G4 function. We believe that the focus on monomeric G4 structures formed by such short sequences is perhaps myopic. Such short sequences for structural studies are often arbitrarily selected and removed from their native genomic sequence context, and then are often changed from their native sequences by base substitutions or deletions intended to optimize the formation of a homogeneous G4 conformation. We believe instead that G-quadruplexes prefer company and that in a longer natural sequence context multiple adjacent G4 units can form to combine into more complex multimeric G4 structures with richer topographies than simple monomeric forms. Bioinformatic searches of the human genome show that longer sequences with the potential for forming multiple G4 units are common. Telomeric DNA, for example, has a single-stranded overhang of hundreds of nucleotides with the requisite repetitive sequence with the potential for formation of multiple G4s. Numerous extended promoter sequences have similar potentials for multimeric G4 formation. X-ray crystallography and NMR methods are challenged by these longer sequences (>30 nt), so other tools are needed to explore the possible multimeric G4 landscape. We have implemented an integrated structural biology approach to address this challenge. This approach integrates experimental biophysical results with atomic-level molecular modeling and molecular dynamics simulations that provide quantitatively testable model structures. In every long sequence we ...

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Section: ■ Perspectivementioning

confidence: 99%

G-quadruplex DNA: A Longer Story

2022

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“…Finally, G4BP is also closely associated with neurodegenerative diseases. For example, the mRNA of genes associated with Parkinson's disease contains stable G4 structures in the 5' UTR regions [85]. These G4s are bound with guanine nucleotide-binding protein-like 1 (GNL1), which may inhibit the translation of the corresponding mRNA.…”

Section: Box 2 the Relationship Between G4-binding Proteins And Diseasesmentioning

confidence: 99%

G-Quadruplex-Protein Interactions: Screening, Characterization and Regulation

Dai

Teng

Zhang

et al. 2022

Preprint

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G-quadruplex (G4) is a kind of peculiar nucleic acid secondary structure formed by DNA or RNA, which is considered as a fundamental feature of the genome. Many proteins can specifically bind to G4 structures. There is increasing evidence that G4-protein interactions involve in the regulation of important cellular processes such as DNA replication, transcription, RNA splicing and translation. Besides, G4-protein interactions have been proved to be potential targets for disease treatment. In order to unravel the detailed bioregulatory mechanisms of G4-binding proteins (G4BPs), biochemical methods for detecting G4-protein interactions with high specificity and sensitivity are highly demanded. Here, we review recent advances in the screening and validation of new G4BPs and bioregulatory tools of G4BPs.

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Vimentin Is at the Heart of Epithelial Mesenchymal Transition (EMT) Mediated Metastasis

Usman

Waseem²,

Nguyen

et al. 2021

Cancers

196

112

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Epithelial-mesenchymal transition (EMT) is a reversible plethora of molecular events where epithelial cells gain the phenotype of mesenchymal cells to invade the surrounding tissues. EMT is a physiological event during embryogenesis (type I) but also happens during fibrosis (type II) and cancer metastasis (type III). It is a multifaceted phenomenon governed by the activation of genes associated with cell migration, extracellular matrix degradation, DNA repair, and angiogenesis. The cancer cells employ EMT to acquire the ability to migrate, resist therapeutic agents and escape immunity. One of the key biomarkers of EMT is vimentin, a type III intermediate filament that is normally expressed in mesenchymal cells but is upregulated during cancer metastasis. This review highlights the pivotal role of vimentin in the key events during EMT and explains its role as a downstream as well as an upstream regulator in this highly complex process. This review also highlights the areas that require further research in exploring the role of vimentin in EMT. As a cytoskeletal protein, vimentin filaments support mechanical integrity of the migratory machinery, generation of directional force, focal adhesion modulation and extracellular attachment. As a viscoelastic scaffold, it gives stress-bearing ability and flexible support to the cell and its organelles. However, during EMT it modulates genes for EMT inducers such as Snail, Slug, Twist and ZEB1/2, as well as the key epigenetic factors. In addition, it suppresses cellular differentiation and upregulates their pluripotent potential by inducing genes associated with self-renewability, thus increasing the stemness of cancer stem cells, facilitating the tumour spread and making them more resistant to treatments. Several missense and frameshift mutations reported in vimentin in human cancers may also contribute towards the metastatic spread. Therefore, we propose that vimentin should be a therapeutic target using molecular technologies that will curb cancer growth and spread with reduced mortality and morbidity.

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Vimentin binds to G-quadruplex repeats found at telomeres and gene promoters

Cited by 3 publications

References 55 publications

G-quadruplex DNA: A Longer Story

G-quadruplex DNA: A Longer Story

G-Quadruplex-Protein Interactions: Screening, Characterization and Regulation

Vimentin Is at the Heart of Epithelial Mesenchymal Transition (EMT) Mediated Metastasis

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