G-quadruplex–forming promoter sequences enable transcriptional activation in response to oxidative stress

Fedeles, Bogdan I.

doi:10.1073/pnas.1701244114

Cited by 21 publications

(17 citation statements)

References 23 publications

(37 reference statements)

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“…Various in silico studies have shown a high frequency of G4 motifs near the promoter regions in both eukaryotic and prokaryotic genomes ( Rawal et al, 2006 ; Huppert and Balasubramanian, 2007 ). Due to their dynamic behavior, G4s at the upstream of the transcription start sites influence the gene expression to a great extent by acting as cis -regulating elements at the transcription and translation level ( Perrone et al, 2013 ; Fedeles, 2017 ; Perrone et al, 2017 ). Therefore, among the highly conserved KP-PGQs, the motifs located at the promoter/upstream regions of the genes were selected for further analysis ( Figure 1C ).…”

Section: Resultsmentioning

confidence: 99%

Conserved G-Quadruplex Motifs in Gene Promoter Region Reveals a Novel Therapeutic Approach to Target Multi-Drug Resistance Klebsiella pneumoniae

et al. 2020

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An opportunistic pathogen, Klebsiella pneumoniae is known to cause life-threating nosocomial infection with a high rate of morbidity and mortality. Evolutions of multi-drug-resistant and hyper-virulent strains of K. pneumoniae make the situation worse. Currently, there is no incisive drug molecule available for drug-resistant hyper-virulent K. pneumoniae infection that emphasizes the need for identification of novel and more promising drug targets in K. pneumoniae . Recently, various non-canonical structures of nucleic acids especially G-quadruplex (G4) motifs have been identified as potential therapeutic targets against several human pathogenic bacteria and viruses including Mycobacterium tuberculosis , Streptococcus pneumoniae , human immunodeficiency virus (HIV), Ebola, and Nipah. Therefore, in present study we screened the K. pneumoniae genomes for identification of evolutionary conserved G4 structure-forming motifs as promising anti-bacterial drug targets. Bioinformatics analysis revealed the presence of six highly conserved G4 motifs in the promoter region of five essential genes that play a critical role in nutrient transport and metabolism. Biophysical studies showed the formation of G4 structure by these conserved motifs. Circular Dichroism melting analysis showed the stabilization of these G4 motifs by a well-known G4-stabilizing agent, BRACO-19. The stabilization of these motifs by BRACO-19 was also able to stop the primer extension process, which is an essential phenomenon for expression of the G4-harboring gene. The addition of G4-specific ligand at low micromolar range was observed to be lethal for the growth of this bacteria and negatively controlled the expression of the G4-harboring genes via G4 structure stabilization. These observations strengthen the formation of G4 structures by the predicted G4 motif in vivo , which can be stabilized by G4 ligands like BRACO-19. This stabilization of G4 structures can attenuate the expression of G4-harboring essential genes and thus play a critical role in the regulation of gene expression. Thus, taking all given result in consideration, for the first time, this study showed the new therapeutic avenue for combating K. pneumoniae infection by characterizing the conserved G4 motifs as promising therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Conserved G-Quadruplex Motifs in Gene Promoter Region Reveals a Novel Therapeutic Approach to Target Multi-Drug Resistance Klebsiella pneumoniae

et al. 2020

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“…Studies have shown that oxidized DNA base damage has a strong positive correlation with elevated oncogene and proinflammatory gene expression (51,52). Of note is that many genes with a G4 promoter are known to be regulated by oxidative stress (53). Recent studies have demonstrated that 8-oxoG or AP sites in G4-forming promoter sequences of VEGF, BCL-2, and KRAS induced up-regulation of the respective genes (37,38,54).…”

Section: Discussionmentioning

confidence: 99%

Endogenous oxidized DNA bases and APE1 regulate the formation of G-quadruplex structures in the genome

Roychoudhury

Pramanik

Harris

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Formation of G-quadruplex (G4) DNA structures in key regulatory regions in the genome has emerged as a secondary structure-based epigenetic mechanism for regulating multiple biological processes including transcription, replication, and telomere maintenance. G4 formation (folding), stabilization, and unfolding must be regulated to coordinate G4-mediated biological functions; however, how cells regulate the spatiotemporal formation of G4 structures in the genome is largely unknown. Here, we demonstrate that endogenous oxidized guanine bases in G4 sequences and the subsequent activation of the base excision repair (BER) pathway drive the spatiotemporal formation of G4 structures in the genome. Genome-wide mapping of occurrence of Apurinic/apyrimidinic (AP) site damage, binding of BER proteins, and G4 structures revealed that oxidized base-derived AP site damage and binding of OGG1 and APE1 are predominant in G4 sequences. Loss of APE1 abrogated G4 structure formation in cells, which suggests an essential role of APE1 in regulating the formation of G4 structures in the genome. Binding of APE1 to G4 sequences promotes G4 folding, and acetylation of APE1, which enhances its residence time, stabilizes G4 structures in cells. APE1 subsequently facilitates transcription factor loading to the promoter, providing mechanistic insight into the role of APE1 in G4-mediated gene expression. Our study unravels a role of endogenous oxidized DNA bases and APE1 in controlling the formation of higher-order DNA secondary structures to regulate transcription beyond its well-established role in safeguarding the genomic integrity.

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“…Guanine bases in the G-quadruplex are sensitive to oxidative damage. A loss of G-quadruplex structure was observed for most oligonucleotides with oxidative damage ( Fedeles, 2017 ). Notably, G-quadruplex structures are more stable in a wider range of temperature and pH than antibodies.…”

Section: The Structure Of G-quadruplexmentioning

confidence: 99%

G-quadruplex based biosensor: A potential tool for SARS-CoV-2 detection

Juhas

Zhang

2020

Biosensors and Bioelectronics

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G-quadruplex is a non-canonical nucleic acid structure formed by the folding of guanine rich DNA or RNA. The conformation and function of G-quadruplex are determined by a number of factors, including the number and polarity of nucleotide strands, the type of cations and the binding targets. Recent studies led to the discovery of additional advantageous attributes of G-quadruplex with the potential to be used in novel biosensors, such as improved ligand binding and unique folding properties. G-quadruplex based biosensor can detect various substances, such as metal ions, organic macromolecules, proteins and nucleic acids with improved affinity and specificity compared to standard biosensors. The recently developed G-quadruplex based biosensors include electrochemical and optical biosensors. A novel G-quadruplex based biosensors also show better performance and broader applications in the detection of a wide spectrum of pathogens, including SARS-CoV-2, the causative agent of COVID-19 disease. This review highlights the latest developments in the field of G-quadruplex based biosensors, with particular focus on the G-quadruplex sequences and recent applications and the potential of G-quadruplex based biosensors in SARS-CoV-2 detection.

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G-quadruplex–forming promoter sequences enable transcriptional activation in response to oxidative stress

Cited by 21 publications

References 23 publications

Conserved G-Quadruplex Motifs in Gene Promoter Region Reveals a Novel Therapeutic Approach to Target Multi-Drug Resistance Klebsiella pneumoniae

Conserved G-Quadruplex Motifs in Gene Promoter Region Reveals a Novel Therapeutic Approach to Target Multi-Drug Resistance Klebsiella pneumoniae

Endogenous oxidized DNA bases and APE1 regulate the formation of G-quadruplex structures in the genome

G-quadruplex based biosensor: A potential tool for SARS-CoV-2 detection

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