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Cited by 69DNA and Nucleic Acid ChemistryTelomeres, Telomerase, and SenescenceAdvanced Glycation End Products research

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Crosstalk between G-quadruplex and ROS

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Wu, Songjiang, Jiang, Ling, Lei, Li, Fu, Chuhan, Huang, Jinhua, Hu, Yibo, Dong, Yumeng, Chen, Jing, Zeng, Qinghai·2023·Cell Death & Disease
DOI 10.1038/s41419-023-05562-0PMC PMC9849334
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Abstract

The excessive production of reactive oxygen species (ROS) can lead to single nucleic acid base damage, DNA strand breakage, inter- and intra-strand cross-linking of nucleic acids, and protein-DNA cross-linking involved in the pathogenesis of cancer, neurodegenerative diseases, and aging. G-quadruplex (G4) is a stacked nucleic acid structure that is ubiquitous across regulatory regions of multiple genes. Abnormal formation and destruction of G4s due to multiple factors, including cations, helicases, transcription factors (TFs), G4-binding proteins, and epigenetic modifications, affect gene replication, transcription, translation, and epigenetic regulation. Due to the lower redox potential of G-rich sequences and unique structural characteristics, G4s are highly susceptible to oxidative damage. Additionally, the formation, stability, and biological regulatory role of G4s are affected by ROS. G4s are involved in regulating gene transcription, translation, and telomere length maintenance, and are therefore key players in age-related degeneration. Furthermore, G4s also mediate the antioxidant process by forming stress granules and activating Nrf2, which is suggestive of their involvement in developing ROS-related diseases. In this review, we have summarized the crosstalk between ROS and G4s, and the possible regulatory mechanisms through which G4s play roles in aging and age-related diseases.

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Fig. 1 Factors affecting G4 structure formation and stability. a Due to the unique negative charge channels in the G4 structure, it is stabilized upon interacting with cations such as K+, Na+, and Li+ through electrostatic forces. b Small molecules and ligands enhance G4 structural stability. c Helicase is involved in regulating the transcription and translation of genes by unwinding G4s. DNA helicases accelerate the unwinding of promoter region G4s and promote the transcription of genes by RNA polymerase (Pol II). RNA G4s are unstable and can be easily unwound by RNA helicases, thereby facilitating the translation process. d Interaction of DNA methylation and G4s: although CpG methylation can block the formation of G4 structures in the region harboring CpG islands, it can recruit TFs to the G4 motifs formed in hypomethylated regions, thereby promoting gene replication and transcription. In addition, the G4s can also reverse CpG methylation and maintain the hypomethylated state.
Fig. 1 Factors affecting G4 structure formation and stability. a Due to the unique negative charge channels in the G4 structure, it is stabilized upon interacting with cations such as K+, Na+, and Li+ through electrostatic forces. b Small molecules and ligands enhance G4 structural stability. c Helicase is involved in regulating the transcription and translation of genes by unwinding G4s. DNA helicases accelerate the unwinding of promoter region G4s and promote the transcription of genes by RNA polymerase (Pol II). RNA G4s are unstable and can be easily unwound by RNA helicases, thereby facilitating the translation process. d Interaction of DNA methylation and G4s: although CpG methylation can block the formation of G4 structures in the region harboring CpG islands, it can recruit TFs to the G4 motifs formed in hypomethylated regions, thereby promoting gene replication and transcription. In addition, the G4s can also reverse CpG methylation and maintain the hypomethylated state.CC BY · PubMed Central
Fig. 2 Factors involved in G4-regulated biological functions. The biological regulation functions of G4s can be affected by transcription factors (TFs), binding proteins(BP), DNA methylation modification, and m6A RNA modification.
Fig. 2 Factors involved in G4-regulated biological functions. The biological regulation functions of G4s can be affected by transcription factors (TFs), binding proteins(BP), DNA methylation modification, and m6A RNA modification.CC BY · PubMed Central
Fig. 3 Role of ROS in G4 formation and stability. ROS oxidizes guanine in G4s and blocks the Hoogsteen hydrogen bonds, which disrupts the thermal stability of the G4 structure (a, b). The guanine bases in the surrounding G-rich region can compensate for the missing guanine and stabilize the G4 structure (a). In addition, G4 can also be modified into other structural forms by altering the G4-forming mode (c). Oxidation of the guanine base in the DNA template chain can also form OG. With the help of RNA polymerase, the RNA chain can form R-loop with the original DNA chain and stabilize the G4 structure (d).
Fig. 3 Role of ROS in G4 formation and stability. ROS oxidizes guanine in G4s and blocks the Hoogsteen hydrogen bonds, which disrupts the thermal stability of the G4 structure (a, b). The guanine bases in the surrounding G-rich region can compensate for the missing guanine and stabilize the G4 structure (a). In addition, G4 can also be modified into other structural forms by altering the G4-forming mode (c). Oxidation of the guanine base in the DNA template chain can also form OG. With the help of RNA polymerase, the RNA chain can form R-loop with the original DNA chain and stabilize the G4 structure (d).CC BY · PubMed Central
Fig. 4 The role of G4 in ROS-mediated regulation of telomere function. OG can activate telomerase by destabilizing DNA G4 structures and inducing Tg structure at thymine (T), which alters the conformation of original G4 to enhance telomerase binding. Meanwhile, mNeil3 can inhibit the formation of Tg, thereby maintaining the stability of the original G4 structure. On the other hand, OG can reduce telomere G4 stability, unfold their structure, and reduce the rejection of POT1, thereby maintaining the integrity and function of DNA telomeres.
Fig. 4 The role of G4 in ROS-mediated regulation of telomere function. OG can activate telomerase by destabilizing DNA G4 structures and inducing Tg structure at thymine (T), which alters the conformation of original G4 to enhance telomerase binding. Meanwhile, mNeil3 can inhibit the formation of Tg, thereby maintaining the stability of the original G4 structure. On the other hand, OG can reduce telomere G4 stability, unfold their structure, and reduce the rejection of POT1, thereby maintaining the integrity and function of DNA telomeres.CC BY · PubMed Central
Fig. 5 The possible mechanisms of ROS-regulated gene transcription depending on promoter G4s. Under oxidative stress, ROS can lead to OG formation in the G-rich region of promoters, which recruits OGG1 to clear OG and form the AP site. APE1 then binds to AP when looped out in the G4 fold to recruit TFs. On the other hand, ROS can also directly attack the G4 structure of the promoter region and form OG, which facilitates the recruitment of PARP1 and the binding of other transcriptional activating proteins to promote gene expression.
Fig. 5 The possible mechanisms of ROS-regulated gene transcription depending on promoter G4s. Under oxidative stress, ROS can lead to OG formation in the G-rich region of promoters, which recruits OGG1 to clear OG and form the AP site. APE1 then binds to AP when looped out in the G4 fold to recruit TFs. On the other hand, ROS can also directly attack the G4 structure of the promoter region and form OG, which facilitates the recruitment of PARP1 and the binding of other transcriptional activating proteins to promote gene expression.CC BY · PubMed Central
Fig. 6 Crosstalk between Nrf2, stress particles, and G4. H2O2-induced ROS promotes Nrf2 protein translation via EF1a interaction with the G4 in Nrf2 5′UTR. Activating downstream antioxidant genes enhances antioxidant capacity and protects normal cells from oxidative damage. Stress-induced DNA damage promotes the formation of DNA-G4 and tiRNA-G4 complex, which trigger SGs assembly by recruiting cytosolic proteins, which involved in antioxidant response and mRNA translation.
Fig. 6 Crosstalk between Nrf2, stress particles, and G4. H2O2-induced ROS promotes Nrf2 protein translation via EF1a interaction with the G4 in Nrf2 5′UTR. Activating downstream antioxidant genes enhances antioxidant capacity and protects normal cells from oxidative damage. Stress-induced DNA damage promotes the formation of DNA-G4 and tiRNA-G4 complex, which trigger SGs assembly by recruiting cytosolic proteins, which involved in antioxidant response and mRNA translation.CC BY · PubMed Central
Fig. 7 ROS regulates oncogene expression depend on G4. The ROS in cancer cells oxidizes guanine residues in the oncogene promoter region or mRNA G4s to OG, which activates the G4-mediated DDR pathway and translation. The transcription and translation of oncogenes promot cancer development.
Fig. 7 ROS regulates oncogene expression depend on G4. The ROS in cancer cells oxidizes guanine residues in the oncogene promoter region or mRNA G4s to OG, which activates the G4-mediated DDR pathway and translation. The transcription and translation of oncogenes promot cancer development.CC BY · PubMed Central
Fig. 8 Proposed involvement of G4 in Neurodegenerative diseases. As a key pathogenic gene of ALS/FTD, G4-forming in the promoter region of C9orf72 can inhibit its transcription. In particular, G4s also recruits hemin, leading to DNA oxidative damage. Formation of G4s in the promoter of Gad1 and Th inhibit their transcription and further affects the synthesis of GABA and Dopamine. G4 formed in the 5′UTR region of α -SnCA, ADAM mRNA, and the 3′UTR region of APP mRNA can directly inhibit translation. However, G4 formed in the BACE1 mRNA 3′UTR region can recruit heterogeneous nuclear ribonucleoprotein H (hnRNPH), promote its translation, and induce the formation of APP, which are involved in the pathogenesis of AD and PD.
Fig. 8 Proposed involvement of G4 in Neurodegenerative diseases. As a key pathogenic gene of ALS/FTD, G4-forming in the promoter region of C9orf72 can inhibit its transcription. In particular, G4s also recruits hemin, leading to DNA oxidative damage. Formation of G4s in the promoter of Gad1 and Th inhibit their transcription and further affects the synthesis of GABA and Dopamine. G4 formed in the 5′UTR region of α -SnCA, ADAM mRNA, and the 3′UTR region of APP mRNA can directly inhibit translation. However, G4 formed in the BACE1 mRNA 3′UTR region can recruit heterogeneous nuclear ribonucleoprotein H (hnRNPH), promote its translation, and induce the formation of APP, which are involved in the pathogenesis of AD and PD.CC BY · PubMed Central

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Research works printed but not linked: 5

  1. Neeley W, Essigmann J. Mechanisms of formation, genotoxicity, and mutation of guanine oxidation products. Chem Res Toxicol. 2006;19:491–505. · DOI · Paper page
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Metadata

Authors
Wu, S., Jiang, L., Lei, L., Fu, C., Huang, J., Hu, Y., Dong, Y., Chen, J., & Zeng, Q.
Affiliations
Central South University (CN)
Corresponding author
  • Chen, Jing
  • Zeng, Qinghai
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2023-01-18
Volume
14
Issue
1
Pages
37-37
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-023-05562-0
PMC
PMC9849334
OpenAlex
W4317234399
Cited by
69
References
229
Citations by year
2026: 17 · 2025: 28 · 2024: 14 · 2023: 10
FWCI
1.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (82103704, 82073420, 82073421, No. 82103704, 82003326, YX202007)
  • Central South University (YX202007)
  • Xiangya Hospital, Central South University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
Keywords
G-quadruplex, reactive oxygen species, oxidative DNA damage, G-rich sequences, stress granules, Nrf2, aging, age-related diseases, transcriptional regulation, telomere maintenance, epigenetic regulation, redox potential
MeSH terms
DNA, Regulatory Sequences, Nucleic Acid, Reactive Oxygen Species, Epigenesis, Genetic, G-Quadruplexes

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