G-Quadruplexes: More Than Just a Kink in Microbial Genomes

Saranathan, Nandhini; Vivekanandan, Perumal

doi:10.1016/j.tim.2018.08.011

Cited by 103 publications

(88 citation statements)

References 101 publications

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“…In humans, they can occur in immunoglobulin switch regions, oncogene promoters, the first introns of genes, and the 5' untranslated regions near translation start sites [4,5,7,12]. These sequences also occur in bacterial genomes [13][14][15][16][17]. Reports vary as to the assessment of the potential for the participation of G-quadruplex structures in the regulation of gene expression in E. coli [13,14,18,19].…”

Section: Introductionmentioning

confidence: 99%

Role of Hfq in Genome Evolution: Instability of G-Quadruplex Sequences in E. coli

et al. 2019

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Certain G-rich DNA repeats can form quadruplex in bacterial chromatin that can present blocks to DNA replication and, if not properly resolved, may lead to mutations. To understand the participation of quadruplex DNA in genomic instability in Escherichia coli (E. coli), mutation rates were measured for quadruplex-forming DNA repeats, including (G 3 T) 4 , (G 3 T) 8 , and a RET oncogene sequence, cloned as the template or nontemplate strand. We evidence that these alternative structures strongly influence mutagenesis rates. Precisely, our results suggest that G-quadruplexes form in E. coli cells, especially during transcription when the G-rich strand can be displaced by R-loop formation. Structure formation may then facilitate replication misalignment, presumably associated with replication fork blockage, promoting genomic instability. Furthermore, our results also evidence that the nucleoid-associated protein Hfq is involved in the genetic instability associated with these sequences. Hfq binds and stabilizes G-quadruplex structure in vitro and likely in cells. Collectively, our results thus implicate quadruplexes structures and Hfq nucleoid protein in the potential for genetic change that may drive evolution or alterations of bacterial gene expression. variable with strands arranged in a parallel, antiparallel, or mixed orientations associated with various glycosidic configurations of guanines [1,[3][4][5]. A single repeat motif can often form multiple structures depending on ionic conditions, as shown for repeats at human telomeres and oncogene promoters [4][5][6][7]. When G-quadruplex structures form in duplex DNA, the C-rich DNA strand complementary to G-quadruplex-forming sequences can form a four stranded i-motif at low pH [8], in which two tracts of cytosines form interdigitated C•C + base pairs [7,9,10] (Figure 1C).Microorganisms 2019, 7, x 2 of 16 quartets are stabilized by monovalent cations. The topology of quadruplex structures is highly variable with strands arranged in a parallel, antiparallel, or mixed orientations associated with various glycosidic configurations of guanines [1,[3][4][5]. A single repeat motif can often form multiple structures depending on ionic conditions, as shown for repeats at human telomeres and oncogene promoters [4][5][6][7]. When G-quadruplex structures form in duplex DNA, the C-rich DNA strand complementary to G-quadruplex-forming sequences can form a four stranded i-motif at low pH [8], in which two tracts of cytosines form interdigitated C•C + base pairs [7,9,10] (Figure 1C).

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Section: Introductionmentioning

confidence: 99%

Role of Hfq in Genome Evolution: Instability of G-Quadruplex Sequences in E. coli

et al. 2019

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“…In bacteria, G4s of DNA are widely distributed, conserved, and enriched in regulatory regions that perform critical functions in replication (30), transcription (31)(32)(33)(34), and translation (32). A DNA-RNA hybrid G-quadruplex formed in bacterial cells mediates transcription termination (35).…”

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RNA G-Quadruplex Structures Mediate Gene Regulation in Bacteria

Shao

Zhang

Umar

et al. 2020

mBio

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Guanine (G)-rich sequences in RNA can fold into diverse RNA G-quadruplex (rG4) structures to mediate various biological functions and cellular processes in eukaryotic organisms. However, the presence, locations, and functions of rG4s in prokaryotes are still elusive. We used QUMA-1, an rG4-specific fluorescent probe, to detect rG4 structures in a wide range of bacterial species both in vitro and in live cells and found rG4 to be an abundant RNA secondary structure across those species. Subsequently, to identify bacterial rG4 sites in the transcriptome, the model Escherichia coli strain and a major human pathogen, Pseudomonas aeruginosa, were subjected to recently developed high-throughput rG4 structure sequencing (rG4-seq). In total, 168 and 161 in vitro rG4 sites were found in E. coli and P. aeruginosa, respectively. Genes carrying these rG4 sites were found to be involved in virulence, gene regulation, cell envelope synthesis, and metabolism. More importantly, biophysical assays revealed the formation of a group of rG4 sites in mRNAs (such as hemL and bswR), and they were functionally validated in cells by genetic (point mutation and lux reporter assays) and phenotypic experiments, providing substantial evidence for the formation and function of rG4s in bacteria. Overall, our study uncovers important regulatory functions of rG4s in bacterial pathogenicity and metabolic pathways and strongly suggests that rG4s exist and can be detected in a wide range of bacterial species. IMPORTANCE G-quadruplex in RNA (rG4) mediates various biological functions and cellular processes in eukaryotic organisms. However, the presence, locations, and functions of rG4 are still elusive in prokaryotes. Here, we found that rG4 is an abundant RNA secondary structure across a wide range of bacterial species. Subsequently, the transcriptome-wide rG4 structure sequencing (rG4-seq) revealed that the model E. coli strain and a major human pathogen, P. aeruginosa, have 168 and 161 in vitro rG4 sites, respectively, involved in virulence, gene regulation, cell envelope, and metabolism. We further verified the regulatory functions of two rG4 sites in bacteria (hemL and bswR). Overall, this finding strongly suggests that rG4s play key regulatory roles in a wide range of bacterial species.

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“…Extensive research indicated that G-quadruplexes were involved in many critical biological processes, including DNA replication [29][30][31][32], telomere regulation [33][34][35][36][37], and RNA translation [38][39][40][41]. It has been proved that G-quadruplexes existed in the viral genome and can regulate the viral biological processes, which made it possible to function as potential drug targets for antiviral strategy [42][43][44]. A study made by Jinzhi Tan et al demonstrated that the SARS-Unique Domain (SUD) within the nsp3 (non-structural protein 3) of SARS coronavirus (SARS-CoV) exhibits the binding preference to the G-quadruplex structure in the human transcript, and potentially interfere with host cell antiviral response [45].…”

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Whole genome identification of potential G-quadruplexes and analysis of the G-quadruplex binding domain for SARS-CoV-2

Zhang

Xiao

et al. 2020

Preprint

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The Coronavirus Disease 2019 pandemic caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) quickly become a global public health emergency. Gquadruplex, one of the non-canonical secondary structures, has shown potential antiviral values. However, little is known about G-quadruplexes on the emerging SARS-CoV-2. Herein, we characterized the potential G-quadruplexes both in the positive and negative-sense viral stands. The identified potential G-quadruplexes exhibits similar features to the G-quadruplexes detected in the human transcriptome. Within some bat and pangolin related beta coronaviruses, the G-quartets rather than the loops are under heightened selective constraints. We also found that the SUD-like sequence is retained in the SARS-CoV-2 genome, while some other coronaviruses that can infect humans are depleted. Further analysis revealed that the SARS-CoV-2 SUD-like sequence is almost conserved among 16,466 SARS-CoV-2 samples. And the SARS-CoV-2 SUDcore-like dimer displayed similar electrostatic potential pattern to the SUD dimer. Considering the potential value of G-quadruplexes to serve as targets in antiviral strategy, we hope our fundamental research could provide new insights for the SARS-CoV-2 drug discovery. Respiratory Syndrome (MERS) in 2012 [2,5], and COVID-19. Scientists identified and sequenced the virus early in this outbreak, and named it SARS-CoV-2[6]. The symptoms of the patients infected with the novel coronavirus vary from person to person, and fever, cough, and fatigue are the most common ones[7-10]. The clinical chest CT (Computed tomography) and nucleic acid testing are the most typical methods of diagnosing 10]. It is worth noting that the recent achievements in AI (Artificial Intelligence) aid diagnosis technology[11] and CRISPR-Cas12-based detection methods [12] are expected to expand the diagnosis of COVID-19. Despite the great efforts of the researchers, so far, no specific clinical drugs or vaccines have been developed to cope with COVID-19. SARS-CoV-2 is a Betacoronavirus within the Coronaviridae family that is the culprit responsible for the COVID-19 pandemic [13,14] (Fig. 1A). Studies have confirmed that SARS-CoV-2 is a positive-sense single-stranded RNA ((+)ssRNA) virus with a total length of approximately 30k. The positive-sense RNA strand of SARS-CoV-2 can serve as a template to produce viral proteins related to replication, structure composition, and other functions or events [15,16]. One of the hotspots is how the SARS-CoV-2 entry the host cells. SARS-CoV-2 has shown a great affinity to the angiotensin-converting enzyme 2 (ACE2), which has been proved to be the binding receptor for SARS-CoV-2 [17,18]. After entering the host cells, the viral genomic RNA will be released to the cytoplasm, and the ORF1a/ORF1ab are subsequently translated into replicase polyproteins of pp1a/pp1ab, which will be cleaved into some non-structural proteins (nsps). These non-structure proteins ultimately form the replicase-transcriptase complex for replication and transcription....

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G-Quadruplexes: More Than Just a Kink in Microbial Genomes

Cited by 103 publications

References 101 publications

Role of Hfq in Genome Evolution: Instability of G-Quadruplex Sequences in E. coli

Role of Hfq in Genome Evolution: Instability of G-Quadruplex Sequences in E. coli

RNA G-Quadruplex Structures Mediate Gene Regulation in Bacteria

Whole genome identification of potential G-quadruplexes and analysis of the G-quadruplex binding domain for SARS-CoV-2

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