QGRS Mapper: a web-based server for predicting G-quadruplexes in nucleotide sequences
TL;DR: A web-based server that predicts quadruplex forming G-rich sequences (QGRS) in nucleotide sequences and features interactive graphic representation of the data is developed, very useful for investigating the functional relevance of G-quadruplex structure, in particular its role in regulating the gene expression by alternative processing.
Abstract: The quadruplex structures formed by guanine-rich nucleic acid sequences have received significant attention recently because of growing evidence for their role in important biological processes and as therapeutic targets. G-quadruplex DNA has been suggested to regulate DNA replication and may control cellular proliferation. Sequences capable of forming G-quadruplexes in the RNA have been shown to play significant roles in regulation of polyadenylation and splicing events in mammalian transcripts. Whether quadruplex structure directly plays a role in regulating RNA processing requires investigation. Computational approaches to study G-quadruplexes allow detailed analysis of mammalian genomes. There are no known easily accessible user-friendly tools that can compute G-quadruplexes in the nucleotide sequences. We have developed a web-based server, QGRS Mapper, that predicts quadruplex forming G-rich sequences (QGRS) in nucleotide sequences. It is a user-friendly application that provides many options for defining and studying G-quadruplexes. It performs analysis of the user provided genomic sequences, e.g. promoter and telomeric regions, as well as RNA sequences. It is also useful for predicting G-quadruplex structures in oligonucleotides. The program provides options to search and retrieve desired gene/nucleotide sequence entries from NCBI databases for mapping G-quadruplexes in the context of RNA processing sites. This feature is very useful for investigating the functional relevance of G-quadruplex structure, in particular its role in regulating the gene expression by alternative processing. In addition to providing data on composition and locations of QGRS relative to the processing sites in the pre-mRNA sequence, QGRS Mapper features interactive graphic representation of the data. The user can also use the graphics module to visualize QGRS distribution patterns among all the alternative RNA products of a gene simultaneously on a single screen. QGRS Mapper can be accessed at http://bioinformatics.ramapo.edu/QGRS/.
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TL;DR: The evidence for G-quadruplexes in gene promoters is described and their potential as therapeutic targets are discussed, as well as progress in the development of strategies to harness this potential through intervention with small-molecule ligands.
Abstract: G-quadruplexes are four-stranded DNA structures that are over-represented in gene promoter regions and are viewed as emerging therapeutic targets in oncology, as transcriptional repression of oncogenes through stabilization of these structures could be a novel anticancer strategy. Many gene promoter G-quadruplexes have physicochemical properties and structural characteristics that might make them druggable, and their structural diversity suggests that a high degree of selectivity might be possible. Here, we describe the evidence for G-quadruplexes in gene promoters and discuss their potential as therapeutic targets, as well as progress in the development of strategies to harness this potential through intervention with small-molecule ligands.
1,420 citations
TL;DR: A high-resolution sequencing–based method is presented to detect G4s in the human genome and observed a high G4 density in functional regions, as well as in genes previously not predicted to contain these structures (such as BRCA2).
Abstract: G-quadruplexes (G4s) are nucleic acid secondary structures that form within guanine-rich DNA or RNA sequences. G4 formation can affect chromatin architecture and gene regulation and has been associated with genomic instability, genetic diseases and cancer progression. Here we present a high-resolution sequencing-based method to detect G4s in the human genome. We identified 716,310 distinct G4 structures, 451,646 of which were not predicted by computational methods. These included previously uncharacterized noncanonical long loop and bulged structures. We observed a high G4 density in functional regions, such as 5' untranslated regions and splicing sites, as well as in genes previously not predicted to contain these structures (such as BRCA2). G4 formation was significantly associated with oncogenes, tumor suppressors and somatic copy number alterations related to cancer development. The G4s identified in this study may therefore represent promising targets for cancer intervention.
797 citations
TL;DR: This review features the progresses in the study of 5′-UTR RNA G-quadruplex-mediated translational control and discusses protein trans-acting factors that have been implicated and the evidence that such RNA motifs have potential as small molecule target.
Abstract: RNA structures in the untranslated regions (UTRs) of mRNAs influence post-transcriptional regulation of gene expression. Much of the knowledge in this area depends on canonical double-stranded RNA elements. There has been considerable recent advancement of our understanding of guanine(G)-rich nucleic acids sequences that form four-stranded structures, called G-quadruplexes. While much of the research has been focused on DNA G-quadruplexes, there has recently been a rapid emergence of interest in RNA G-quadruplexes, particularly in the 5'-UTRs of mRNAs. Collectively, these studies suggest that RNA G-quadruplexes exist in the 5'-UTRs of many genes, including genes of clinical interest, and that such structural elements can influence translation. This review features the progresses in the study of 5'-UTR RNA G-quadruplex-mediated translational control. It covers computational analysis, cell-free, cell-based and chemical biology studies that have sought to elucidate the roles of RNA G-quadruplexes in both cap-dependent and -independent regulation of mRNA translation. We also discuss protein trans-acting factors that have been implicated and the evidence that such RNA motifs have potential as small molecule target. Finally, we close the review with a perspective on the future challenges in the field of 5'-UTR RNA G-quadruplex-mediated translation regulation.
548 citations
Cites background from "QGRS Mapper: a web-based server for..."
...In addition to mRNA 50-UTRs, RNA PQSs have also been computationally identified in 30-UTRs, and in pre-mRNAs near splicing, transcription termination and polyadenylation sites, indicating that RNA G-quadruplexes might also regulate other stages of RNA metabolism (42,43,74)....
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TL;DR: This review highlights how recent methodological advances in the identification and characterization of G-quadruplexes in vivo as well as in vitro, and at a much higher resolution and throughput, have opened new doors to investigate the potential functions and applications in basic and applied biosciences.
274 citations
Cites methods from "QGRS Mapper: a web-based server for..."
...For intramolecular quadruplexes, many algorithms have been published over the past decade to predict the potential formation of G-quadruplexes directly from DNA sequence, including QuadParser [39], QGRS Mapper [40], G4P Calculator [41], QuadBase [42] and most recently, G4 Hunter [43]: their relative features are reviewed in [44]....
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TL;DR: This work identified a cis-acting DNA sequence near the antigenically variable pilin locus of the human pathogen, Neisseria gonorrhoeae, which constitutes a recombination initiation sequence/structure that directs gene conversion to a specific chromosomal locus.
Abstract: Pathogens can utilize DNA recombination to promote antigenic variation of surface structures to avoid immune detection We identified a cis-acting DNA sequence near the antigenically variable pilin locus of the human pathogen, Neisseria gonorrhoeae This 16 base pair G-rich sequence was required for pilin antigenic variation and formed a guanine quartet (G4) structure in vitro Individual mutations that disrupted the structure also blocked pilin antigenic variation and prevented nicks required for recombination from occurring within the G4 region A compound that binds and stabilizes G4 structures also inhibited pilin antigenic variation and prevented nicks from occurring on the G-rich strand This site constitutes a recombination initiation sequence/structure that directs gene conversion to a specific chromosomal locus
274 citations
References
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TL;DR: There is a significant repression of quadruplexes in the coding strand of exonic regions, which suggests that quadruplex-forming patterns are disfavoured in sequences that will form RNA.
Abstract: Guanine-rich DNA sequences of a particular form have the ability to fold into four-stranded structures called G-quadruplexes. In this paper, we present a working rule to predict which primary sequences can form this structure, and describe a search algorithm to identify such sequences in genomic DNA. We count the number of quadruplexes found in the human genome and compare that with the figure predicted by modelling DNA as a Bernoulli stream or as a Markov chain, using windows of various sizes. We demonstrate that the distribution of loop lengths is significantly different from what would be expected in a random case, providing an indication of the number of potentially relevant quadruplex-forming sequences. In particular, we show that there is a significant repression of quadruplexes in the coding strand of exonic regions, which suggests that quadruplex-forming patterns are disfavoured in sequences that will form RNA.
1,493 citations
"QGRS Mapper: a web-based server for..." refers background or result in this paper
...Although, G-quadruplexes have been surveyed in the human genome with such techniques (34,35), there are no known user-friendly computational tools easily accessible to the public....
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...This restriction on the length of the sequences being considered is in agreement with recent literature (34,35)....
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TL;DR: These genome-wide data provide experimental evidence and tissue distributions for thousands of known and novel alternative splicing events and indicate that at least 74% of human multi-exon genes are alternatively spliced.
Abstract: Alternative pre-messenger RNA (pre-mRNA) splicing plays important roles in development, physiology, and disease, and more than half of human genes are alternatively spliced. To understand the biological roles and regulation of alternative splicing across different tissues and stages of development, systematic methods are needed. Here, we demonstrate the use of microarrays to monitor splicing at every exon-exon junction in more than 10,000 multi-exon human genes in 52 tissues and cell lines. These genome-wide data provide experimental evidence and tissue distributions for thousands of known and novel alternative splicing events. Adding to previous studies, the results indicate that at least 74% of human multi-exon genes are alternatively spliced.
1,488 citations
"QGRS Mapper: a web-based server for..." refers background in this paper
...Over two-thirds of human genes are thought to undergo alternative splicing (32)....
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TL;DR: This Review integrates and summarizes knowledge gained from areas ranging from structural biology and medicinal chemistry to supramolecular chemistry and nanotechnology, with emphasis on G-quartet structure, function, and molecular recognition.
Abstract: Molecular self-assembly is central to many processes in both biology and supramolecular chemistry. The G-quartet, a hydrogen-bonded macrocycle formed by cation-templated assembly of guanosine, was first identified in 1962 as the basis for the aggregation of 5'-guanosine monophosphate. We now know that many nucleosides, oligonucleotides, and synthetic derivatives form a rich array of functional G-quartets. The G-quartet surfaces in areas ranging from structural biology and medicinal chemistry to supramolecular chemistry and nanotechnology. This Review integrates and summarizes knowledge gained from these different areas, with emphasis on G-quartet structure, function, and molecular recognition.
1,432 citations
TL;DR: From examination of the optical properties of the gel and investigation of the structure of fibers obtained from the gel by drying, it is concluded that, at least in the case of the 5' isomer, the phenomenon may be explained as being due to helix formation by the guanylic acid.
Abstract: In 1910, Bang' reported that concentrated solutions of guanylic acid formed a gel. We have also observed that concentrated solutions (25.0 mg/ml) of guanylic acid (GMP) at pH 5 are extremely viscous and, if cooled, form a clear gel. Less concentrated solutions also gel on cooling but assume a more normal viscosity at room temperature. From examination of the optical properties of the gel and investigation of the structure of fibers obtained from the gel by drying, we have concluded that, at least in the case of the 5' isomer, the phenomenon may be explained as being due to helix formation by the guanylic acid. A possible structure is presented for this helix.
1,327 citations
"QGRS Mapper: a web-based server for..." refers background in this paper
...The structure consists of stacked G-tetrads, which are square co-planar arrays of four guanine bases each (6)....
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TL;DR: A large-scale study provides important insights into the mechanism of polyadenylation in mammalian species and represents a genomic view of the regulation of gene expression by alternative polyadenyation.
Abstract: mRNA polyadenylation is a critical cellular process in eukaryotes. It involves 3' end cleavage of nascent mRNAs and addition of the poly(A) tail, which plays important roles in many aspects of the cellular metabolism of mRNA. The process is controlled by various cis-acting elements surrounding the cleavage site, and their binding factors. In this study, we surveyed genome regions containing cleavage sites [herein called poly(A) sites], for 13,942 human and 11,155 mouse genes. We found that a great proportion of human and mouse genes have alternative polyadenylation ( approximately 54 and 32%, respectively). The conservation of alternative polyadenylation type or polyadenylation configuration between human and mouse orthologs is statistically significant, indicating that alternative polyadenylation is widely employed by these two species to produce alternative gene transcripts. Genes belonging to several functional groups, indicated by their Gene Ontology annotations, are biased with respect to polyadenylation configuration. Many poly(A) sites harbor multiple cleavage sites (51.25% human and 46.97% mouse sites), leading to heterogeneous 3' end formation for transcripts. This implies that the cleavage process of polyadenylation is largely imprecise. Different types of poly(A) sites, with regard to their relative locations in a gene, are found to have distinct nucleotide composition in surrounding genomic regions. This large-scale study provides important insights into the mechanism of polyadenylation in mammalian species and represents a genomic view of the regulation of gene expression by alternative polyadenylation.
916 citations
"QGRS Mapper: a web-based server for..." refers background in this paper
...More than half of human genes are known to have alternative polyadenylation (31)....
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