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Molecular Cancer Feb 2021DNA and RNA can fold into a variety of alternative conformations. In recent years, a particular nucleic acid structure was discussed to play a role in malignant... (Review)
Review
DNA and RNA can fold into a variety of alternative conformations. In recent years, a particular nucleic acid structure was discussed to play a role in malignant transformation and cancer development. This structure is called a G-quadruplex (G4). G4 structure formation can drive genome instability by creating mutations, deletions and stimulating recombination events. The importance of G4 structures in the characterization of malignant cells was currently demonstrated in breast cancer samples. In this analysis a correlation between G4 structure formation and an increased intratumor heterogeneity was identified. This suggests that G4 structures might allow breast cancer stratification and supports the identification of new personalized treatment options. Because of the stability of G4 structures and their presence within most human oncogenic promoters and at telomeres, G4 structures are currently tested as a therapeutic target to downregulate transcription or to block telomere elongation in cancer cells. To date, different chemical molecules (G4 ligands) have been developed that aim to target G4 structures. In this review we discuss and compare G4 function and relevance for therapeutic approaches and their impact on cancer development for three cancer entities, which differ significantly in their amount and type of mutations: pancreatic cancer, leukemia and malignant melanoma. G4 structures might present a promising new strategy to individually target tumor cells and could support personalized treatment approaches in the future.
Topics: Antineoplastic Agents; DNA, Neoplasm; G-Quadruplexes; Genomic Instability; Humans; Ligands; Mutation; Neoplasms; Promoter Regions, Genetic; Structure-Activity Relationship
PubMed: 33632214
DOI: 10.1186/s12943-021-01328-4 -
Proceedings of the National Academy of... May 2023Maintaining the health of the proteome is a critical cellular task. Recently, we found G-quadruplex (G4) nucleic acids are especially potent at preventing protein...
Maintaining the health of the proteome is a critical cellular task. Recently, we found G-quadruplex (G4) nucleic acids are especially potent at preventing protein aggregation in vitro and could at least indirectly improve the protein folding environment of . However, the roles of G4s in protein folding were not yet explored. Here, through in vitro protein folding experiments, we discover that G4s can accelerate protein folding by rescuing kinetically trapped intermediates to both native and near-native folded states. Time-course folding experiments in further demonstrate that these G4s primarily improve protein folding quality in as opposed to preventing protein aggregation. The ability of a short nucleic acid to rescue protein folding opens up the possibility of nucleic acids and ATP-independent chaperones to play considerable roles in dictating the ultimate folding fate of proteins.
Topics: G-Quadruplexes; Escherichia coli; Protein Aggregates; Nucleic Acids; Protein Folding
PubMed: 37155907
DOI: 10.1073/pnas.2216308120 -
Molecules (Basel, Switzerland) Aug 2019G-quadruplexes are noncanonical nucleic acid structures formed from stacked guanine tetrads. They are frequently used as building blocks and functional elements in... (Review)
Review
G-quadruplexes are noncanonical nucleic acid structures formed from stacked guanine tetrads. They are frequently used as building blocks and functional elements in fields such as synthetic biology and also thought to play widespread biological roles. G-quadruplexes are often studied as monomers, but can also form a variety of higher-order structures. This increases the structural and functional diversity of G-quadruplexes, and recent evidence suggests that it could also be biologically important. In this review, we describe the types of multimeric topologies adopted by G-quadruplexes and highlight what is known about their sequence requirements. We also summarize the limited information available about potential biological roles of multimeric G-quadruplexes and suggest new approaches that could facilitate future studies of these structures.
Topics: DNA; G-Quadruplexes; Models, Molecular; Molecular Structure; Nucleic Acid Conformation; RNA; Structure-Activity Relationship; Telomere
PubMed: 31450559
DOI: 10.3390/molecules24173074 -
Molecules (Basel, Switzerland) Aug 2022Tetrads (or quartets) are arrangements of four nucleobases commonly involved in the stability of four-stranded nucleic acids structures. Four-stranded or quadruplex... (Review)
Review
Tetrads (or quartets) are arrangements of four nucleobases commonly involved in the stability of four-stranded nucleic acids structures. Four-stranded or quadruplex structures have attracted enormous attention in the last few years, being the most extensively studied guanine quadruplex (G-quadruplex). Consequently, the G-tetrad is the most common and well-known tetrad. However, this is not the only possible arrangement of four nucleobases. A number of tetrads formed by the different nucleobases have been observed in experimental structures. In most cases, these tetrads occur in the context of G-quadruplex structures, either inserted between G-quartets, or as capping elements at the sides of the G-quadruplex core. In other cases, however, non-G tetrads are found in more unusual four stranded structures, such as i-motifs, or different types of peculiar fold-back structures. In this report, we review the diversity of these non-canonical tetrads, and the structural context in which they have been found.
Topics: G-Quadruplexes; Guanine; Models, Molecular; Nucleic Acid Conformation
PubMed: 36014524
DOI: 10.3390/molecules27165287 -
International Journal of Molecular... Jan 2023The repeat expansions are the main genetic cause of various neurodegeneration diseases. More than ten kinds of repeat sequences with different lengths, locations, and... (Review)
Review
The repeat expansions are the main genetic cause of various neurodegeneration diseases. More than ten kinds of repeat sequences with different lengths, locations, and structures have been confirmed in the past two decades. G-rich repeat sequences, such as CGG and GGGGCC, are reported to form functional G-quadruplexes, participating in many important bioprocesses. In this review, we conducted an overview concerning the contribution of G-quadruplex in repeat expansion disorders and summarized related mechanisms in current pathological studies, including the increasing genetic instabilities in replication and transcription, the toxic RNA foci formed in neurons, and the loss/gain function of proteins and peptides. Furthermore, novel strategies targeting G-quadruplex repeats were developed based on the understanding of disease mechanism. Small molecules and proteins binding to G-quadruplex in repeat expansions were investigated to protect neurons from dysfunction and delay the progression of neurodegeneration. In addition, the effects of environment on the stability of G-quadruplex were discussed, which might be critical factors in the pathological study of repeat expansion disorders.
Topics: Humans; G-Quadruplexes; Amyotrophic Lateral Sclerosis; Proteins; Peptides; Repetitive Sequences, Nucleic Acid
PubMed: 36768697
DOI: 10.3390/ijms24032375 -
Molecules (Basel, Switzerland) Oct 2019G-quadruplexes constitute a unique class of nucleic acid structures formed by G-rich oligonucleotides of DNA- or RNA-type. Depending on their chemical nature, loops... (Review)
Review
G-quadruplexes constitute a unique class of nucleic acid structures formed by G-rich oligonucleotides of DNA- or RNA-type. Depending on their chemical nature, loops length, and localization in the sequence or structure molecularity, G-quadruplexes are highly polymorphic structures showing various folding topologies. They may be formed in the human genome where they are believed to play a pivotal role in the regulation of multiple biological processes such as replication, transcription, and translation. Thus, natural G-quadruplex structures became prospective targets for disease treatment. The fast development of systematic evolution of ligands by exponential enrichment (SELEX) technologies provided a number of G-rich aptamers revealing the potential of G-quadruplex structures as a promising molecular tool targeted toward various biologically important ligands. Because of their high stability, increased cellular uptake, ease of chemical modification, minor production costs, and convenient storage, G-rich aptamers became interesting therapeutic and diagnostic alternatives to antibodies. In this review, we describe the recent advances in the development of G-quadruplex based aptamers by focusing on the therapeutic and diagnostic potential of this exceptional class of nucleic acid structures.
Topics: Aptamers, Nucleotide; Drug Delivery Systems; Early Diagnosis; G-Quadruplexes; Humans
PubMed: 31640176
DOI: 10.3390/molecules24203781 -
The FEBS Journal Jun 2022G-quadruplexes are four-stranded helical nucleic acid structures characterized by stacked tetrads of guanosine bases. These structures are widespread throughout... (Review)
Review
G-quadruplexes are four-stranded helical nucleic acid structures characterized by stacked tetrads of guanosine bases. These structures are widespread throughout mammalian genomic DNA and RNA transcriptomes, and prevalent across all tissues. The role of G-quadruplexes in cancer is well-established, but there has been a growing exploration of these structures in the development and homeostasis of normal tissue. In this review, we focus on the roles of G-quadruplexes in directing gene expression in the nervous system, including the regulation of gene transcription, mRNA processing, and trafficking, as well as protein translation. The role of G-quadruplexes and their molecular interactions in the pathology of neurological diseases is also examined. Outside of cancer, there has been only limited exploration of G-quadruplexes as potential intervention targets to treat disease or injury. We discuss studies that have used small-molecule ligands to manipulate G-quadruplex stability in order to treat disease or direct neural stem/progenitor cell proliferation and differentiation into therapeutically relevant cell types. Understanding the many roles that G-quadruplexes have in the nervous system not only provides critical insight into fundamental molecular mechanisms that control neurological function, but also provides opportunities to identify novel therapeutic targets to treat injury and disease.
Topics: Animals; DNA; G-Quadruplexes; Mammals; Nervous System; Protein Biosynthesis; RNA
PubMed: 33905176
DOI: 10.1111/febs.15900 -
Genes May 2023G-quadruplexes (G4s) have long been implicated in the regulation of chromatin packaging and gene expression. These processes require or are accelerated by the separation... (Review)
Review
G-quadruplexes (G4s) have long been implicated in the regulation of chromatin packaging and gene expression. These processes require or are accelerated by the separation of related proteins into liquid condensates on DNA/RNA matrices. While cytoplasmic G4s are acknowledged scaffolds of potentially pathogenic condensates, the possible contribution of G4s to phase transitions in the nucleus has only recently come to light. In this review, we summarize the growing evidence for the G4-dependent assembly of biomolecular condensates at telomeres and transcription initiation sites, as well as nucleoli, speckles, and paraspeckles. The limitations of the underlying assays and the remaining open questions are outlined. We also discuss the molecular basis for the apparent permissive role of G4s in the in vitro condensate assembly based on the interactome data. To highlight the prospects and risks of G4-targeting therapies with respect to the phase transitions, we also touch upon the reported effects of G4-stabilizing small molecules on nuclear biomolecular condensates.
Topics: G-Quadruplexes; Biomolecular Condensates; Cell Nucleus; RNA; Proteins
PubMed: 37239436
DOI: 10.3390/genes14051076 -
Nucleic Acids Research Oct 2015'If G-quadruplexes form so readily in vitro, Nature will have found a way of using them in vivo' (Statement by Aaron Klug over 30 years ago).During the last decade,... (Review)
Review
'If G-quadruplexes form so readily in vitro, Nature will have found a way of using them in vivo' (Statement by Aaron Klug over 30 years ago).During the last decade, four-stranded helical structures called G-quadruplex (or G4) have emerged from being a structural curiosity observed in vitro, to being recognized as a possible nucleic acid based mechanism for regulating multiple biological processes in vivo. The sequencing of many genomes has revealed that they are rich in sequence motifs that have the potential to form G-quadruplexes and that their location is non-random, correlating with functionally important genomic regions. In this short review, we summarize recent evidence for the in vivo presence and function of DNA and RNA G-quadruplexes in various cellular pathways including DNA replication, gene expression and telomere maintenance. We also highlight remaining open questions that will have to be addressed in the future.
Topics: DNA; DNA Replication; G-Quadruplexes; Genome, Human; Genomic Instability; Humans; Protein Biosynthesis; RNA; Telomere; Transcription, Genetic
PubMed: 26350216
DOI: 10.1093/nar/gkv862 -
Nucleic Acids Research Feb 2021G-quadruplex (G4) DNA structures with a left-handed backbone progression have unique and conserved structural features. Studies on sequence dependency of the structures...
G-quadruplex (G4) DNA structures with a left-handed backbone progression have unique and conserved structural features. Studies on sequence dependency of the structures revealed the prerequisites and some minimal motifs required for left-handed G4 formation. To extend the boundaries, we explore the adaptability of left-handed G4s towards the existence of bulges. Here we present two X-ray crystal structures and an NMR solution structure of left-handed G4s accommodating one, two and three bulges. Bulges in left-handed G4s show distinct characteristics as compared to those in right-handed G4s. The elucidation of intricate structural details will help in understanding the possible roles and limitations of these unique structures.
Topics: Crystallography, X-Ray; DNA; G-Quadruplexes; Models, Molecular; Nuclear Magnetic Resonance, Biomolecular; Nucleotide Motifs; Sugars
PubMed: 33503265
DOI: 10.1093/nar/gkaa1259