scholarly journals Investigation of the Stereochemical-Dependent DNA and RNA Binding of Arginine-Based Nucleopeptides

Symmetry ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 567
Author(s):  
Stefano Tomassi ◽  
Francisco Franco Montalban ◽  
Rosita Russo ◽  
Ettore Novellino ◽  
Anna Messere ◽  
...  
Keyword(s):  
Rna Binding ◽  
Md Simulations ◽  
Spectroscopic Studies ◽  
Rna Molecules ◽  
Dna And Rna ◽  
Hybrid Complex ◽  
Potential Structure ◽  
Rna Complexes ◽  
Stable Hybrid

Nucleopeptides represent an intriguing class of nucleic acid analogues, in which nucleobases are placed in a peptide structure. The incorporation of D- and/or L-amino acids in nucleopeptide molecules allows the investigation of the role of backbone stereochemistry in determining the formation of DNA and RNA hybrids. Circular Dichroism (CD) spectroscopic studies indicated the nucleopeptide as having fully l-backbone configuration-formed stable hybrid complexes with RNA molecules. Molecular Dynamics (MD) simulations suggested a potential structure of the complex resulting from the interaction between the l-nucleopeptide and RNA strand. From this study, both the backbone (ionics and H-bonds) and nucleobases (pairing and π-stacking) of the chiral nucleopeptide appeared to be involved in the hybrid complex formation, highlighting the key role of the backbone stereochemistry in the formation of the nucleopeptide/RNA complexes.

scholarly journals RNA binding to human METTL3-METTL14 restricts N6-deoxyadenosine methylation of DNA in vitro

2022 ◽  
Author(s):  
Shan Qi ◽  
Javier Mota ◽  
Siu-Hong Chan ◽  
Johanna Villarreal ◽  
Nan Dai ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Rna Binding ◽  
Methyl Group ◽  
High Affinity ◽  
Methylation Of Dna ◽  
Dna And Rna ◽  
Close Proximity ◽  
Methylation Activity

Methyltransferase like-3 (METTL3) and METTL14 complex transfers a methyl group from S-adenosyl-L-methionine to N6 amino group of adenosine bases in RNA (m6A) and DNA (m6dA). Emerging evidence highlights a role of METTL3-METTL14 in the chromatin context, especially in processes where DNA and RNA are held in close proximity. However, a mechanistic framework about specificity for substrate RNA/DNA and their interrelationship remain unclear. By systematically studying methylation activity and binding affinity to a number of DNA and RNA oligos with different propensities to form inter- or intra-molecular duplexes or single-stranded molecules in vitro, we uncover an inverse relationship for substrate binding and methylation and show that METTL3-METTL14 preferentially catalyzes the formation of m6dA in single-stranded DNA (ssDNA), despite weaker binding affinity to DNA. In contrast, it binds structured RNAs with high affinity, but methylates the target adenosine in RNA (m6A) much less efficiently than it does in ssDNA. We also show that METTL3-METTL14-mediated methylation of DNA is largely restricted by structured RNA elements prevalent in long noncoding and other cellular RNAs.

scholarly journals Hnrnpul1 loss of function affects skeletal and limb development

2020 ◽  
Author(s):  
Danielle L Blackwell ◽  
Sherri D Fraser ◽  
Oana Caluseriu ◽  
Claudia Vivori ◽  
Paul MK Gordon ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Limb Development ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Nucleic Acid Binding ◽  
Loss Of Function ◽  
Zebrafish Model ◽  
Dna And Rna ◽  
Developmental Role

AbstractMutations in RNA binding proteins can lead to pleiotropic phenotypes including craniofacial, skeletal, limb and neurological symptoms. Heterogeneous Nuclear Ribonucleoproteins (hnRNPs) are involved in nucleic acid binding, transcription and splicing through direct binding to DNA and RNA, or through interaction with other proteins in the spliceosome. Here, we show a developmental role for hnrnpul1 in zebrafish fin and craniofacial development, and in adult onset scoliosis. Furthermore, we demonstrate a role of hnrnpul1 in alternative splicing regulation. In two siblings with congenital limb malformations, whole exome sequencing detected a frameshift variant in HNRNPUL1; the developmental role of this gene in humans has not been explored. Our data suggest an important developmental role of hnRNPUL1 in both zebrafish and humans. Although there are differences in phenotypes between species, our data suggests potential conservation of ancient regulatory circuits involving hnRNPUL1 in these phylogenetically distant species.Summary statementA zebrafish model of loss of Hnrnpul1 shows alternative splicing defects and results in limb growth, craniofacial tendon, and skeletal anomalies.

scholarly journals The Etiological Agent of Lyme Disease, Borrelia burgdorferi, Appears To Contain Only a Few Small RNA Molecules

2004 ◽  
Vol 186 (24) ◽  
pp. 8472-8477 ◽  
Author(s):  
Yngve Östberg ◽  
Ignas Bunikis ◽  
Sven Bergström ◽  
Jörgen Johansson
Keyword(s):  
Borrelia Burgdorferi ◽  
Small Rna ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Rnase E ◽  
Regulatory Pathways ◽  
Rna Molecules ◽  
Small Regulatory Rnas ◽  
Regulatory Rnas

ABSTRACT Small regulatory RNAs (sRNAs) have recently been shown to be the main controllers of several regulatory pathways. The function of sRNAs depends in many cases on the RNA-binding protein Hfq, especially for sRNAs with an antisense function. In this study, the genome of Borrelia burgdorferi was subjected to different searches for sRNAs, including direct homology and comparative genomics searches and ortholog- and annotation-based search strategies. Two new sRNAs were found, one of which showed complementarity to the rpoS region, which it possibly controls by an antisense mechanism. The role of the other sRNA is unknown, although observed complementarities against particular mRNA sequences suggest an antisense mechanism. We suggest that the low level of sRNAs observed in B. burgdorferi is at least partly due to the presumed lack of both functional Hfq protein and RNase E activity.

scholarly journals Hrp59, an hnRNP M protein in Chironomus and Drosophila, binds to exonic splicing enhancers and is required for expression of a subset of mRNAs

2005 ◽  
Vol 168 (7) ◽  
pp. 1013-1025 ◽  
Author(s):  
Eva Kiesler ◽  
Manuela E. Hase ◽  
David Brodin ◽  
Neus Visa
Keyword(s):  
Rna Binding ◽  
M Protein ◽  
Nuclear Pore ◽  
Binding Domains ◽  
Mrna Targets ◽  
Modular Domain ◽  
Exonic Splicing Enhancers ◽  
Rna Complexes

Here, we study an insect hnRNP M protein, referred to as Hrp59. Hrp59 is relatively abundant, has a modular domain organization containing three RNA-binding domains, is dynamically recruited to transcribed genes, and binds to premRNA cotranscriptionally. Using the Balbiani ring system of Chironomus, we show that Hrp59 accompanies the mRNA from the gene to the nuclear envelope, and is released from the mRNA at the nuclear pore. The association of Hrp59 with transcribed genes is not proportional to the amount of synthesized RNA, and in vivo Hrp59 binds preferentially to a subset of mRNAs, including its own mRNA. By coimmunoprecipitation of Hrp59–RNA complexes and microarray hybridization against Drosophila whole-genome arrays, we identify the preferred mRNA targets of Hrp59 in vivo and show that Hrp59 is required for the expression of these target mRNAs. We also show that Hrp59 binds preferentially to exonic splicing enhancers and our results provide new insights into the role of hnRNP M in splicing regulation.

scholarly journals NF90/ILF3 is a transcription factor that promotes proliferation over differentiation by hierarchical regulation in K562 erythroleukemia cells

2017 ◽  
Author(s):  
Ting-Hsuan Wu ◽  
Lingfang Shi ◽  
Jessika Adrian ◽  
Minyi Shi ◽  
Ramesh V. Nair ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Rna Splicing ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
K562 Cells ◽  
Dna And Rna ◽  
Erythroleukemia Cells ◽  
Binding Factor ◽  
Differential Gene

ABSTRACTNF90 and splice variant NF110 are DNA‐ and RNA-binding proteins encoded by the Interleukin enhancer-binding factor 3 (ILF3) gene that regulate RNA splicing, stabilization and export. The role of NF90 in regulating transcription as a DNA-binding protein has not been comprehensively characterized. Here, ENCODE ChIP-seq identified 9,081 genomic sites specifically bound by NF90/110 in K562 cells. One third of binding sites occurred at promoters of annotated genes. NF90/110 binding colocalized with chromatin marks associated with active promoters and strong enhancers. Comparison with 150 ENCODE ChIP-seq experiments revealed that NF90 clustered with transcription factors exhibiting preference for promoters over enhancers (POLR2A, MYC, YY1). Differential gene expression analysis following shRNA knockdown of NF90 in K562 cells revealed that NF90 directly activates transcription factors that drive growth and proliferation (EGR1, MYC), while attenuating differentiation along erythroid lineage (KLF1). NF90/110 binds chromatin to hierarchically regulate transcription factors to promote proliferation and suppress differentiation.

scholarly journals Exosome-Mediated Signaling in Epithelial to Mesenchymal Transition and Tumor Progression

2018 ◽  
Vol 8 (1) ◽  
pp. 26 ◽  
Author(s):  
Alice Conigliaro ◽  
Carla Cicchini
Keyword(s):  
Tumor Progression ◽  
Intercellular Communication ◽  
Epithelial To Mesenchymal Transition ◽  
Current Knowledge ◽  
Cell Communication ◽  
Therapeutic Approaches ◽  
Mesenchymal Transition ◽  
Rna Molecules ◽  
Dna And Rna

Growing evidence points to exosomes as key mediators of cell–cell communication, by transferring their specific cargo (e.g., proteins, lipids, DNA and RNA molecules) from producing to receiving cells. In cancer, the regulation of the exosome-mediated intercellular communication may be reshaped, inducing relevant changes in gene expression of recipient cells in addition to microenvironment alterations. Notably, exosomes may deliver signals able to induce the transdifferentiation process known as Epithelial-to-Mesenchymal Transition (EMT). In this review, we summarize recent findings on the role of exosomes in tumor progression and EMT, highlighting current knowledge on exosome-mediated intercellular communication in tumor-niche establishment, migration, invasion, and metastasis processes. This body of evidence suggests the relevance of taking into account exosome-mediated signaling and its multifaceted aspects to develop innovative anti-tumoral therapeutic approaches.

scholarly journals How short RNAs impact the human ribonuclease Dicer activity: putative regulatory feedback-loops and other RNA-mediated mechanisms controlling microRNA processing

2017 ◽  
Vol 63 (4) ◽  
Author(s):  
Natalia Koralewska ◽  
Weronika Hoffmann ◽  
Maria Pokornowska ◽  
Marek Cezary Milewski ◽  
Andrea Lipinska ◽  
...  
Keyword(s):  
Rna Binding ◽  
Feedback Loops ◽  
Small Interfering Rnas ◽  
Binding Studies ◽  
Hairpin Rna ◽  
Rna Molecules ◽  
Short Rnas ◽  
Microrna Processing

Ribonuclease Dicer plays a pivotal role in RNA interference pathways by processing long double-stranded RNAs and single-stranded hairpin RNA precursors into small interfering RNAs (siRNAs) and microRNAs (miRNAs), respectively. While details of Dicer regulation by variety of proteins are being elucidated, less is known about non-protein factors; e.g. RNA molecules, that may influence the enzyme activity. Therefore, we decided to investigate the problem of whether the RNA molecules can function not only as Dicer substrates but also as its regulators.Our previous in vitro studies indicated that the activity of human Dicer can be influenced by short RNA molecules that either bind to Dicer or interact with its substrates, or both. Those studies were carried out with commercial Dicer preparations. Nevertheless, such preparations are usually not homogeneous enough to carry out more detailed RNA-binding studies. Therefore, we have established our own system for the production of human Dicer in insect cells. In this manuscript we characterize the RNA-binding and RNA-cleavage properties of the obtained preparation. We demonstrate that Dicer can efficiently bind single-stranded RNAs longer than ~20-nucleotides. Consequently, we revisit possible scenarios of Dicer regulation by single-stranded RNA species ranging from ~10- to ~60-nucleotides, in the context of their binding with the enzyme. Finally, we show that siRNA/miRNA-sized RNAs may affect miRNA production either by binding to Dicer or by regulatory feedback-loops. Altogether, our studies suggest a broad regulatory role of short RNAs in Dicer functioning.

scholarly journals In silico study predicts a key role of RNA-binding domains 3 and 4 in nucleolin-miRNA interactions.

2021 ◽  
Author(s):  
Avdar San ◽  
Dario Palmieri ◽  
Anjana Saxena ◽  
Shaneen Singh
Keyword(s):  
In Silico ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mirna Precursor ◽  
Structural Determinants ◽  
Rna Molecules ◽  
Cellular Processes ◽  
Binding Domains ◽  
Rna Binding Domains

RNA binding proteins (RBPs) regulate many important cellular processes through their interactions with RNA molecules. RBPs are critical for post-transcriptional mechanisms keeping gene regulation in a fine equilibrium. Conversely, dysregulation of RBPs and RNA metabolism pathways is an established hallmark of tumorigenesis. Human nucleolin (NCL) is a multifunctional RBP that interacts with different types of RNA molecules, in part through its four RNA binding domains (RBDs). Particularly, NCL interacts directly with microRNAs (miRNAs) and is involved in their aberrant processing linked with many cancers, including breast cancer. Nonetheless, molecular details of the NCL-miRNA interaction remain obscure. In this study, we used an in silico approach to characterize how NCL targets miRNAs and whether this specificity is imposed by a definite RBD-interface. Here, we present structural models of NCL-RBDs and miRNAs, as well as predict scenarios of NCL- miRNA interactions generated using docking algorithms. Our study suggests a predominant role of NCL RBDs 3 and 4 (RBD3-4) in miRNA binding. We provide detailed analyses of specific motifs/residues at the NCL-substrate interface in both these RBDs and miRNAs. Finally, we propose that the evolutionary emergence of more than two RBDs in NCL in higher organisms coincides with its additional role/s in miRNA processing. Our study shows that RBD3-4 display sequence/structural determinants to specifically recognize miRNA precursor molecules. Moreover, the insights from this study can ultimately support the design of novel antineoplastic drugs aimed at regulating NCL-dependent biological pathways with a causal role in tumorigenesis.

scholarly journals Cancer-Associated circRNA–miRNA–mRNA Regulatory Networks: A Meta-Analysis

2021 ◽  
Vol 8 ◽  
Author(s):  
Shaheerah Khan ◽  
Atimukta Jha ◽  
Amaresh C. Panda ◽  
Anshuman Dixit
Keyword(s):  
Regulatory Networks ◽  
Target Genes ◽  
Rna Binding ◽  
Meta Analysis ◽  
Study Data ◽  
Circular Rnas ◽  
Rna Molecules ◽  
Sequencing Technologies ◽  
Non Coding Rnas

Recent advances in sequencing technologies and the discovery of non-coding RNAs (ncRNAs) have provided new insights in the molecular pathogenesis of cancers. Several studies have implicated the role of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and recently discovered circular RNAs (circRNAs) in tumorigenesis and metastasis. Unlike linear RNAs, circRNAs are highly stable and closed-loop RNA molecules. It has been established that circRNAs regulate gene expression by controlling the functions of miRNAs and RNA-binding protein (RBP) or by translating into proteins. The circRNA–miRNA–mRNA regulatory axis is associated with human diseases, such as cancers, Alzheimer’s disease, and diabetes. In this study, we explored the interaction among circRNAs, miRNAs, and their target genes in various cancers using state-of-the-art bioinformatics tools. We identified differentially expressed circRNAs, miRNAs, and mRNAs on multiple cancers from publicly available data. Furthermore, we identified many crucial drivers and tumor suppressor genes in the circRNA–miRNA–mRNA regulatory axis in various cancers. Together, this study data provide a deeper understanding of the circRNA–miRNA–mRNA regulatory mechanisms in cancers.

scholarly journals The Integral Role of RNA in Stress Granule Formation and Function

2021 ◽  
Vol 9 ◽  
Author(s):  
Danae Campos-Melo ◽  
Zachary C. E. Hawley ◽  
Cristian A. Droppelmann ◽  
Michael J. Strong
Keyword(s):  
Rna Binding ◽  
Viral Infections ◽  
Acute Stress ◽  
Rna Binding Proteins ◽  
Protein Composition ◽  
Current Evidence ◽  
Granule Formation ◽  
Rna Molecules ◽  
Rna Granules

Stress granules (SGs) are phase-separated, membraneless, cytoplasmic ribonucleoprotein (RNP) assemblies whose primary function is to promote cell survival by condensing translationally stalled mRNAs, ribosomal components, translation initiation factors, and RNA-binding proteins (RBPs). While the protein composition and the function of proteins in the compartmentalization and the dynamics of assembly and disassembly of SGs has been a matter of study for several years, the role of RNA in these structures had remained largely unknown. RNA species are, however, not passive members of RNA granules in that RNA by itself can form homo and heterotypic interactions with other RNA molecules leading to phase separation and nucleation of RNA granules. RNA can also function as molecular scaffolds recruiting multivalent RBPs and their interactors to form higher-order structures. With the development of SG purification techniques coupled to RNA-seq, the transcriptomic landscape of SGs is becoming increasingly understood, revealing the enormous potential of RNA to guide the assembly and disassembly of these transient organelles. SGs are not only formed under acute stress conditions but also in response to different diseases such as viral infections, cancer, and neurodegeneration. Importantly, these granules are increasingly being recognized as potential precursors of pathological aggregates in neurodegenerative diseases. In this review, we examine the current evidence in support of RNA playing a significant role in the formation of SGs and explore the concept of SGs as therapeutic targets.

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