The regulation and functions of DNA and RNA G-quadruplexes

Varshney, Dhaval; Spiegel, Jochen; Zyner, Katherine G.; Tannahill, David; Balasubramanian, Shankar

doi:10.1038/s41580-020-0236-x

Cited by 919 publications

(860 citation statements)

References 214 publications

(265 reference statements)

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“…The importance of these genomic secondary structures has been abundantly studied during the last years (11)(12)(13)(14)(15)(16). They have been found to be regulatory elements in the human genome implicated in key functions such as telomere maintenance and genome transcription regulation, replication and repair (17). G4 structures have also been identified in fungi (18)(19)(20)(21), bacteria (22)(23)(24)(25)(26) and parasites (27)(28)(29)(30)(31)(32).…”

Section: Introductionmentioning

confidence: 99%

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Exploring G and C-quadruplex structures as potential targets against the severe acute respiratory syndrome coronavirus 2

Belmonte-Reche

Serrano

González

et al. 2020

Preprint

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In this paper we report the analysis of the 2019-nCoV genome and related viruses using an upgraded version of the open-source algorithm G4-iM Grinder. This version improves the functionality of the software, including an easy way to determine the potential biological features affected by the candidates found. The quadruplex definitions of the algorithm were optimized for 2019-nCoV. Using a lax quadruplex definition ruleset, which accepts amongst other parameters two residue G- and C-tracks, hundreds of potential quadruplex candidates were discovered. These sequences were evaluated by their in vitro formation probability, their position in the viral RNA, their uniqueness and their conservation rates (calculated in over three thousand different COVID-19 clinical cases and sequenced at different times and locations during the ongoing pandemic). These results were compared sequentially to other Coronaviridae members, other Group IV (+)ssRNA viruses and the entire realm. Sequences found in common with other species were further analyzed and characterized. Sequences with high scores unique to the 2019-nCoV were studied to investigate the variations amongst similar species. Quadruplex formation of the best candidates was then confirmed experimentally. Using NMR and CD spectroscopy, we found several highly stable RNA quadruplexes that may be suitable theranostic targets against the 2019-nCoV.

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Section: Introductionmentioning

confidence: 99%

“…A. Top scoring PQS (Score ≥ 30, entry 1 to 7) and PiMS (Score ≤ -30, entry 8 to17) found in the 2019-nCoV ordered by their localization in the genome. In blue and in dark yellow, the G-and C-runs respectively, and in red, the loops.…”

mentioning

confidence: 99%

Exploring G and C-quadruplex structures as potential targets against the severe acute respiratory syndrome coronavirus 2

Belmonte-Reche

Serrano

González

et al. 2020

Preprint

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“…Intriguingly, a report from Yongyi Shen et al showed that SARS-CoV-2 might be the recombination product of Bat-CoV-RaTG13-like virus and Pangolin-CoV-like virus [24]. G-quadruplexes are the non-canonical nucleic acid structures usually formed in G-rich regions both in DNA and RNA strands [25][26][27]. The G-quadruplex is formed by stacking G-quartets (Fig.…”

mentioning

confidence: 99%

“…1B) on top of each other, in which the four guanines making up a G-quartets are connected via Hoogsteen pairs (Fig. 1C) [25][26][27][28]. 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].…”

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confidence: 99%

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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“…We have also identified an enrichment of G-rich sequences near the vicinity of LS2 target exons. Various roles have implicated the regulation of RNA function by G quadruplex formation, highlighting a regulatory role of this local structure in the cellular context [95][96][97][98][99] . Recent studies show the presence of G4-forming motifs in the vicinity of the splice sites and also highlight their influence on splicing regulation 60,73 strongly suggesting that the formation of G4 structures could provide another degree of regulation in alternative pre-mRNA splicing.…”

Section: Discussionmentioning

confidence: 99%

Structural evolution of the tissue-specific U2AF2 paralog and alternative splicing factor LS2

Kawale¹,

Taliaferro²,

Kang³

et al. 2020

Preprint

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The Drosophila melanogaster LS2 protein is a tissue-specific paralog of U2AF2 that mediates testis-specific alternative splicing. In order to understand the structural mechanisms underlying the distinct RNA binding specificity we determined the solution structures of the LS2 RNA recognition motif (RRM) domains and characterized their interaction with cis-regulatory guanosine-rich RNA motifs found in intron regions upstream of alternatively spliced exons. We show that the guanosine-rich RNA adopts a G quadruplex (G4) fold in vitro. The LS2 tandem RRMs adopt canonical RRM folds that are connected by a 38-residue linker that harbors a small helical motif α0. The LS2 RRM2 domain and the α0 helix in the interdomain linker mediate interactions with the G4 RNA. The functional importance of these unique molecular features in LS2 is validated by mutational analysis in vitro and RNA splicing assays in vivo. RNA sequencing data confirm the enrichment of G4-forming LS2 target motifs near LS2-affected exons. Our data indicate a role of G quadruplex structures as cis-regulatory motifs in introns for the regulation of alternative splicing, that engage non-canonical interactions with a tandem RRM protein. These results highlight the intriguing molecular evolution of a tissue-specific splicing factor from its conserved U2AF2 paralog as a result of (retro-) gene duplication in D. melanogaster.

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The regulation and functions of DNA and RNA G-quadruplexes

Cited by 919 publications

References 214 publications

Exploring G and C-quadruplex structures as potential targets against the severe acute respiratory syndrome coronavirus 2

Exploring G and C-quadruplex structures as potential targets against the severe acute respiratory syndrome coronavirus 2

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

Structural evolution of the tissue-specific U2AF2 paralog and alternative splicing factor LS2

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