scholarly journals Interplay of Guanine Oxidation and G-Quadruplex Folding in Gene Promoters

2019 ◽  
Vol 142 (3) ◽  
pp. 1115-1136 ◽  
Author(s):  
Aaron M. Fleming ◽  
Cynthia J. Burrows
Keyword(s):  
Gene Promoters ◽  
Guanine Oxidation ◽  
G Quadruplex

scholarly journals G-quadruplex–R-loop interactions and the mechanism of anticancer G-quadruplex binders

2020 ◽  
Vol 48 (21) ◽  
pp. 11942-11957
Author(s):  
Giulia Miglietta ◽  
Marco Russo ◽  
Giovanni Capranico
Keyword(s):  
Selective Inhibition ◽  
Telomere Maintenance ◽  
Published Data ◽  
Gene Promoters ◽  
Untranslated Exon ◽  
G Quadruplex ◽  
Functional Consequences ◽  
Hoogsteen Hydrogen Bonds

Abstract Genomic DNA and cellular RNAs can form a variety of non-B secondary structures, including G-quadruplex (G4) and R-loops. G4s are constituted by stacked guanine tetrads held together by Hoogsteen hydrogen bonds and can form at key regulatory sites of eukaryote genomes and transcripts, including gene promoters, untranslated exon regions and telomeres. R-loops are 3-stranded structures wherein the two strands of a DNA duplex are melted and one of them is annealed to an RNA. Specific G4 binders are intensively investigated to discover new effective anticancer drugs based on a common rationale, i.e.: the selective inhibition of oncogene expression or specific impairment of telomere maintenance. However, despite the high number of known G4 binders, such a selective molecular activity has not been fully established and several published data point to a different mode of action. We will review published data that address the close structural interplay between G4s and R-loops in vitro and in vivo, and how these interactions can have functional consequences in relation to G4 binder activity. We propose that R-loops can play a previously-underestimated role in G4 binder action, in relation to DNA damage induction, telomere maintenance, genome and epigenome instability and alterations of gene expression programs.

scholarly journals Biophysical and X-ray structural studies of the (GGGTT)3GGG G-quadruplex in complex with N-methyl mesoporphyrin IX

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0241513
Author(s):  
Linda Yingqi Lin ◽  
Sawyer McCarthy ◽  
Barrett M. Powell ◽  
Yanti Manurung ◽  
Irene M. Xiang ◽  
...  
Keyword(s):  
Tight Binding ◽  
Water Soluble ◽  
Gene Promoters ◽  
X Ray ◽  
Binding Stoichiometry ◽  
Biological Studies ◽  
G Quadruplex ◽  
Small Molecule Ligands ◽  
Fluorescence Titrations ◽  
Water Soluble Porphyrin

The G-quadruplex (GQ) is a well-studied non-canonical DNA structure formed by G-rich sequences found at telomeres and gene promoters. Biological studies suggest that GQs may play roles in regulating gene expression, DNA replication, and DNA repair. Small molecule ligands were shown to alter GQ structure and stability and thereby serve as novel therapies, particularly against cancer. In this work, we investigate the interaction of a G-rich sequence, 5’-GGGTTGGGTTGGGTTGGG-3’ (T1), with a water-soluble porphyrin, N-methyl mesoporphyrin IX (NMM) via biophysical and X-ray crystallographic studies. UV-vis and fluorescence titrations, as well as a Job plot, revealed a 1:1 binding stoichiometry with an impressively tight binding constant of 30–50 μM-1 and ΔG298 of -10.3 kcal/mol. Eight extended variants of T1 (named T2 –T9) were fully characterized and T7 was identified as a suitable candidate for crystallographic studies. We solved the crystal structures of the T1- and T7-NMM complexes at 2.39 and 2.34 Å resolution, respectively. Both complexes form a 5’-5’ dimer of parallel GQs capped by NMM at the 3’ G-quartet, supporting the 1:1 binding stoichiometry. Our work provides invaluable details about GQ-ligand binding interactions and informs the design of novel anticancer drugs that selectively recognize specific GQs and modulate their stability for therapeutic purposes.

scholarly journals Oxidative DNA damage is epigenetic by regulating gene transcription via base excision repair

2016 ◽  
Author(s):  
Aaron M. Fleming ◽  
Yun Ding ◽  
Cynthia J. Burrows
Keyword(s):  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Gene Activation ◽  
Gene Promoters ◽  
Abasic Site ◽  
Protein Activity ◽  
Modified Dna ◽  
G Quadruplex ◽  
Base Excision

AbstractReactive oxygen species (ROS) have emerged as important cellular signaling agents for survival. Herein, we demonstrate that ROS-mediated oxidation of DNA to yield 8-oxo-7,8-dihydroguanine (OG) in gene promoters is a signaling agent for gene activation. Enhanced gene expression occurs when OG is formed in guanine-rich, potential G-quadruplex sequences (PQS) in promoter coding strands to initiate base excision repair (BER) by 8-oxoguanine DNA glycosylase (OGG1) yielding an abasic site (AP). The AP enables melting of the duplex to unmask the PQS to adopt a G-quadruplex fold in which apurinic/apyrimidinic endonuclease 1 (APE1) binds, but inefficiently cleaves, the AP for activation of VEGF or NTHL1 genes. This concept allowed identification of 61 human DNA repair genes that might be activated by this mechanism. Identification of the oxidatively-modified DNA base OG as guiding protein activity on the genome and altering cellular phenotype ascribes an epigenetic role to OG.

scholarly journals Vimentin binds to G-quadruplex repeats found at telomeres and gene promoters

2021 ◽  
Author(s):  
Silvia Ceschi ◽  
Michele Berselli ◽  
Mery Giantin ◽  
Stefano Toppo ◽  
Barbara Spolaore ◽  
...  
Keyword(s):  
Regulation Of Gene Expression ◽  
Enrichment Analysis ◽  
Intermediate Filament Protein ◽  
Gene Promoters ◽  
Genome Maintenance ◽  
Core Promoters ◽  
Lamin B ◽  
G Quadruplex ◽  
And Migration ◽  
Filament Protein

G-quadruplex (G4) structures that can form at guanine-rich genomic sites, including telomeres and gene promoters, are actively involved in genome maintenance, replication, and transcription, through finely tuned interactions with protein networks. In the present study, we identified the intermediate filament protein Vimentin as a binder with nanomolar affinity for those G-rich sequences that give rise to at least two adjacent G4 units, named G4 repeats. This interaction is supported by the N-terminal domains of soluble Vimentin tetramers. The selectivity of Vimentin for G4 repeats vs individual G4s provides an unprecedented result. Based on GO enrichment analysis performed on genes having putative G4 repeats within their core promoters, we suggest that Vimentin recruitment at these sites may contribute to the regulation of gene expression during cell development and migration, possibly by reshaping the local higher-order genome topology, as already reported for lamin B.

scholarly journals CpG Methylation Changes G-Quadruplex Structures Derived from Gene Promoters and Interaction with VEGF and SP1

Molecules ◽  
2018 ◽  
Vol 23 (4) ◽  
pp. 944 ◽  
Author(s):  
Kaori Tsukakoshi ◽  
Shiori Saito ◽  
Wataru Yoshida ◽  
Shinichi Goto ◽  
Kazunori Ikebukuro
Keyword(s):  
Cpg Methylation ◽  
Gene Promoters ◽  
G Quadruplex

scholarly journals G-Quadruplex Modulation of SP1 Functional Binding Sites at the KIT Proximal Promoter

2020 ◽  
Vol 22 (1) ◽  
pp. 329
Author(s):  
Silvia Da Ros ◽  
Giulia Nicoletto ◽  
Riccardo Rigo ◽  
Silvia Ceschi ◽  
Eleonora Zorzan ◽  
...  
Keyword(s):  
Physiological Mechanism ◽  
Structural Features ◽  
Site Directed Mutagenesis ◽  
Proximal Promoter ◽  
Pharmacological Intervention ◽  
Gene Promoters ◽  
Control Of Gene Expression ◽  
G Quadruplex ◽  
Fine Control ◽  
Different Levels

The regulation of conformational arrangements of gene promoters is a physiological mechanism that has been associated with the fine control of gene expression. Indeed, it can drive the time and the location for the selective recruitment of proteins of the transcriptional machinery. Here, we address this issue at the KIT proximal promoter where three G-quadruplex forming sites are present (kit1, kit2 and kit*). On this model, we focused on the interplay between G-quadruplex (G4) formation and SP1 recruitment. By site directed mutagenesis, we prepared a library of plasmids containing mutated sequences of the WT KIT promoter that systematically exploited different G4 formation attitudes and SP1 binding properties. Our transfection data showed that the three different G4 sites of the KIT promoter impact on SP1 binding and protein expression at different levels. Notably, kit2 and kit* structural features represent an on-off system for KIT expression through the recruitment of transcription factors. The use of two G4 binders further helps to address kit2-kit* as a reliable target for pharmacological intervention.

scholarly journals Location dependence of the transcriptional response of a potential G-quadruplex in gene promoters under oxidative stress

2019 ◽  
Vol 47 (10) ◽  
pp. 5049-5060 ◽  
Author(s):  
Aaron M Fleming ◽  
Judy Zhu ◽  
Yun Ding ◽  
Cynthia J Burrows
Keyword(s):  
Oxidative Stress ◽  
Transcriptional Response ◽  
Gene Promoters ◽  
G Quadruplex

Four-stranded DNA: cancer, gene regulation and drug development

2007 ◽  
Vol 365 (1861) ◽  
pp. 2969-2984 ◽  
Author(s):  
Julian Leon Huppert
Keyword(s):  
Clinical Trials ◽  
Anticancer Agents ◽  
Double Helix ◽  
Biological Significance ◽  
Gene Promoters ◽  
Cancer Gene ◽  
Stability Prediction ◽  
Structural Form ◽  
Future Directions ◽  
G Quadruplex

DNA can form many structures other than the famous double helix. In particular, guanine-rich DNA of particular sequences can form four-stranded structures, called G-quadruplexes. This article describes the structural form of these sequences, techniques for predicting which sequences can fold up in this manner and efforts towards stability prediction. It then discusses the biological significance of these structures, focusing on their importance in telomeric regions at the end of chromosomes, and their existence in gene promoters and mRNA, where they may be involved with regulating transcription and translation, respectively. Ligands that are capable of selectively binding to these structures are introduced and described, as are DNA aptamers that form G-quadruplex structures; both of these classes of compound have been investigated as anticancer agents in clinical trials. The growing use of G-quadruplexes in the nanotechnology field is also outlined. The article concludes with an analysis of future directions the field may take, with some proposals for further important studies.

scholarly journals Oxidative DNA damage is epigenetic by regulating gene transcription via base excision repair

2017 ◽  
Vol 114 (10) ◽  
pp. 2604-2609 ◽  
Author(s):  
Aaron M. Fleming ◽  
Yun Ding ◽  
Cynthia J. Burrows
Keyword(s):  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Luciferase Reporter ◽  
Luciferase Expression ◽  
Gene Promoters ◽  
Modified Dna ◽  
G Quadruplex ◽  
Base Excision ◽  
The Impact

Reactive oxygen species (ROS) have emerged as important cellular-signaling agents for cellular survival. Herein, we demonstrate that ROS-mediated oxidation of DNA to yield 8-oxo-7,8-dihydroguanine (OG) in gene promoters is a signaling agent for gene activation. Enhanced gene expression occurs when OG is formed in guanine-rich, potential G-quadruplex–forming sequences (PQS) in promoter-coding strands, initiating base excision repair (BER) by 8-oxoguanine DNA glycosylase (OGG1), yielding an abasic site (AP). The AP enables melting of the duplex to unmask the PQS, adopting a G-quadruplex fold in which apurinic/apyrimidinic endonuclease 1 (APE1) binds, but inefficiently cleaves, the AP for activation of vascular endothelial growth factor (VEGF) or endonuclease III-like protein 1 (NTHL1) genes. These details were mapped via synthesis of OG and AP analogs at single-nucleotide precision within the promoter of a luciferase reporter system. The reporters were analyzed in human and mouse cells while selectively knocking out or down critical BER proteins to identify the impact on luciferase expression. Identification of the oxidatively modified DNA base OG to guide BER activity in a gene promoter and impact cellular phenotype ascribes an epigenetic role to OG.

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