Ligands stimulating antitumour immunity as the next G-quadruplex challenge

Miglietta, Giulia; Marinello, Jessica; Russo, Marco; Capranico, Giovanni

doi:10.1186/s12943-022-01649-y

Cited by 44DNA and Nucleic Acid ChemistryImmunotherapy and Immune ResponsesMetal complexes synthesis and properties

Ligands stimulating antitumour immunity as the next G-quadruplex challenge

Open access

Miglietta, Giulia, Marinello, Jessica, Russo, Marco, Capranico, Giovanni·2022·Molecular Cancer

DOI 10.1186/s12943-022-01649-yPMC PMC9482198

Open this paper in CoChat — free account Open PDF

Abstract

G-quadruplex (G4) binders have been investigated to discover new anticancer drugs worldwide in past decades. As these ligands are generally not highly cytotoxic, the discovery rational was mainly based on increasing the cell-killing potency. Nevertheless, no G4 binder has been shown yet to be effective in cancer patients. Here, G4 binder activity at low dosages will be discussed as a critical feature to discover ligands with therapeutic effects in cancer patients. Specific effects of G4 binders al low doses have been reported to occur in cancer and normal cells. Among them, genome instability and the stimulation of cytoplasmic processes related to autophagy and innate immune response open to the use of G4 binders as immune-stimulating agents. Thus, we propose a new rational of drug discovery, which is not based on cytotoxic potency but rather on immune gene activation at non-cytotoxic dosage.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1186/s12943-022-01649-y

Cites

144 of 144 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

G4-stabilizing ligand therapies mostly rely on increased genomic instability in cancer cells to slow or stop cancer progression and cell growth.
“which mostly rely on an increased genomic instability in cancer cells to slow or stop cancer progression and cell growth (83).”
From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [83]
The Background (page unavailable) says several G4 binders can arrest DNA replication, causing DNA damage and genome instability, and that past research pursued cytotoxic ligands. But the Conclusions and the section on G4 stabilization (pages unavailable) describe other mechanisms and note that cancer cells can survive binder-induced DNA breaks. The paper does not establish that G4-ligand therapies *mostly rely* on genomic instability to slow or stop cancer progression or cell growth. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Deregulated or ligand-induced G4-formation is associated with the activation of DNA-damage responses, implying that aberrant G4-formation triggers similar pathways as DNA-damage.
“deregulated or ligand-induced G4-formation is associated with the activation of DNA-damage responses, implying that aberrant G4-formation triggers similar pathways as DNA-damage (83).”
From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [83]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Publisher's Note
van der Togt, H. (2003) · Journal of Network and Computer Applications · doi:10.1016/s1084-8045(02)00061-9 · Cited by 302,548
Inflammation and cancer: triggers, mechanisms, and consequences
Greten, F. R., & Grivennikov, S. I. (2019) · Immunity · doi:10.1016/j.immuni.2019.06.025 · Cited by 3,806 · cited 1× · see citing works
“Unfortunately, many tumours do not respond to them or become unresponsive at relapse [95], highlighting”
Background
The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications
Zhang, Y., & Zhang, Z. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-0488-6 · Cited by 2,815 · cited 1× · see citing works
“and autophagy in cancer cells The latest and successful progresses in medical oncology have been achieved by the development of effective anticancer immunotherapy [91, 92].”
Background
Delivery technologies for cancer immunotherapy
Riley, R., June, C. H., Langer, R., & Mitchell, M. J. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-018-0006-z · Cited by 2,621 · cited 1× · see citing works
“Immunotherapies aimed to enhance T-cell responses by targeting inhibitory pathways using immune checkpoint inhibitors [93] or by stimulation using chimeric antigen receptor T cells (CAR-T) or bispecific antibodies [94].”
Background
Quadruplex DNA: sequence, topology and structure
Burge, S., Parkinson, G. N., Hazel, P., Todd, A. K., & Neidle, S. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl655 · Cited by 2,404 · cited 1× · see citing works
“Experimental and bioinformatic data showed that the canonical consensus of potential G4-forming sequences (PQS) is G≥3N1–7G≥3N1–7G≥3N1–7G≥3 [1], even though a majority of sequences shown to form a G4 structure can escape the consensus [2].”
Background
Control of adaptive immunity by the innate immune system
Iwasaki, A., & Medzhitov, R. (2015) · Nature Immunology · doi:10.1038/ni.3123 · Cited by 2,160 · cited 1× · see citing works
“The T-cell activation depends on the innate immune response which is the first barrier of defence to monitor and detect molecular alterations in cancer cells [96].”
Background
Quantitative visualization of DNA G-quadruplex structures in human cells
Biffi, G., Tannahill, D., McCafferty, J., & Balasubramanian, S. (2013) · Nature Chemistry · doi:10.1038/nchem.1548 · Cited by 2,152 · cited 1× · see citing works
“G4 folding in vivo has been visualized by using specific antibodies (BG4) in fixed cells [6] or fluorescent and radioactive probes in living cells [7–10].”
Method
A Landscape of Pharmacogenomic Interactions in Cancer
Iorio, F., Knijnenburg, T. A., Vis, D. J., Bignell, G. R., Menden, M. P., Schubert, M., Aben, N., Gonçalves, E., Barthorpe, S., Lightfoot, H., et al. (2016) · Cell · doi:10.1016/j.cell.2016.06.017 · Cited by 2,090 · cited 1× · see citing works
“(GDSC) database [40], which includes information from around one thousands cancer cell lines (www.”
Background
STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors
Woo, S.-R., Fuertes, M. B., Corrales, L., Spranger, S., Furdyna, M. J., Leung, M. Y. K., Duggan, R., Wang, Y., Barber, G. N., Fitzgerald, K. A., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.10.017 · Cited by 1,917 · cited 1× · see citing works
“The STING-dependent type I interferon response plays a role in T-cell tumour recruitment fundamental to elicit the immune adaptive tumour surveillance, as STING activation could mediate the tumour response to the checkpoint inhibitors as shown by the reduced efficacy of the anti-CTLA4 and anti-PDL-1 treatment in STING…”
Background
Addiction to Oncogenes--the Achilles Heal of Cancer
Weinstein, I. (2002) · Science · doi:10.1126/science.1073096 · Cited by 1,753 · cited 1× · see citing works
“Many efforts have been focused on trying to inhibit single oncogene expression to exploit the tumour addiction phenomena [47] and enhance G4-binder cancer cell killing potency.”
Background
cGAS surveillance of micronuclei links genome instability to innate immunity
Mackenzie, K. J., Carroll, P., Martin, C.-A., Murina, O., Fluteau, A., Simpson, D. J., Olova, N., Sutcliffe, H., Rainger, J. K., Leitch, A., et al. (2017) · Nature · doi:10.1038/nature23449 · Cited by 1,752 · cited 1× · see citing works
“Micronuclei are recognized by specific PRR or cytoplasmic DNA sensors like cGAS [98, 99], and cGAS bound to micronuclei leads to STING activation, which is a pivotal player in promoting Type I Interferon and other immune genes [100] as silencing, deletion or chemically inhibition of STING abolished immune genes respon…”
Background
Hallmarks of response, resistance, and toxicity to immune checkpoint blockade
Morad, G., Helmink, B. A., Sharma, P., & Wargo, J. A. (2021) · Cell · doi:10.1016/j.cell.2021.09.020 · Cited by 1,648 · cited 1× · see citing works
“Immunotherapies aimed to enhance T-cell responses by targeting inhibitory pathways using immune checkpoint inhibitors [93] or by stimulation using chimeric antigen receptor T cells (CAR-T) or bispecific antibodies [94].”
Background
Targeting G-quadruplexes in gene promoters: a novel anticancer strategy?
Balasubramanian, S., Hurley, L., & Neidle, S. (2011) · Nature reviews. Drug discovery · doi:10.1038/nrd3428 · Cited by 1,550 · cited 1× · see citing works
“Successively, the observation that G4s are enriched in many genomic regulatory regions, oncogene promoters and open chromatin regions, revealed new opportunities for ligands to selectively target G4s regulating oncogene expression [46].”
Background
Mitotic progression following DNA damage enables pattern recognition within micronuclei
Harding, S. M., Benci, J. L., Irianto, J., Discher, D. E., Minn, A. J., & Greenberg, R. A. (2017) · Nature · doi:10.1038/nature23470 · Cited by 1,508 · cited 2× · see citing works
“Micronuclei are recognized by specific PRR or cytoplasmic DNA sensors like cGAS [98, 99], and cGAS bound to micronuclei leads to STING activation, which is a pivotal player in promoting Type I Interferon and other immune genes [100] as silencing, deletion or chemically inhibition of STING abolished immune genes respon…”
Background
G-quadruplexes and their regulatory roles in biology
Rhodes, D., & Lipps, H. J. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv862 · Cited by 1,494 · cited 1× · see citing works
“RNA structures Since the first demonstration of a G4 structure in vitro [3], research has been focused at the demonstration that G4s exist in living cells in both the genome and transcriptome [51].”
Background
DNA secondary structures: stability and function of G-quadruplex structures
Bochman, M. L., Paeschke, K., & Zakian, V. A. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3296 · Cited by 1,449 · see citing works
Combination strategies with PD-1/PD-L1 blockade: current advances and future directions
Yi, M., Zheng, X., Niu, M., Zhu, S., Ge, H., & Wu, K. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01489-2 · Cited by 1,445 · cited 1× · see citing works
“The STING-dependent type I interferon response plays a role in T-cell tumour recruitment fundamental to elicit the immune adaptive tumour surveillance, as STING activation could mediate the tumour response to the checkpoint inhibitors as shown by the reduced efficacy of the anti-CTLA4 and anti-PDL-1 treatment in STING…”
Background
Helix formation by guanylic acid.
Gellert, M., Lipsett, M., & Davies, D. R. (1962) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.48.12.2013 · Cited by 1,430 · cited 2× · see citing works
“The ability of a G-rich strand to adopt a G4 secondary structure was demonstrated in 1962 [3] and, after decades of studies, we now know that runs of DNA and RNA guanines can adopt very polymorphic G4 structures.”
Background
Cytoplasmic chromatin triggers inflammation in senescence and cancer
Dou, Z., Ghosh, K., Vizioli, M. G., Zhu, J., Sen, P., Wangensteen, K. J., Simithy, J., Lan, Y., Lin, Y., Zhou, Z., et al. (2017) · Nature · doi:10.1038/nature24050 · Cited by 1,335 · cited 1× · see citing works
“In addition, it has to be considered that high expression levels of STING can exhibit a strong NF-kB signature that can drive tumorigenesis through chronic inflammation [137].”
Background
Autophagy induction via STING trafficking is a primordial function of the cGAS pathway
Gui, X., Yang, H., Li, T., Tan, X., Shi, P., Li, M., Du, F., & Chen, Z. J. (2019) · Nature · doi:10.1038/s41586-019-1006-9 · Cited by 1,269 · cited 1× · see citing works
“This is consistent with other findings showing that the cGAS-STING pathway activates the autophagy process through a TANK-binding kinase 1 (TBK1) independent mechanism [108] and that cGAS is a critical regulator of inflammation and autophagy in Huntington’s disease [109].”
Result
The regulation and functions of DNA and RNA G-quadruplexes
Varshney, D., Spiegel, J., Zyner, K. G., Tannahill, D., & Balasubramanian, S. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0236-x · Cited by 1,265 · cited 2× · see citing works
“For instances, G4s have been shown to exert beneficial effects on homeostatic molecular processes such as telomere maintenance, immunoglobulin recombination, and regulation of gene transcription and mRNA translation [9, 15].”
Background
Double-Strand Break Repair-Independent Role for BRCA2 in Blocking Stalled Replication Fork Degradation by MRE11
Schlacher, K., Christ, N., Siaud, N., Egashira, A., Wu, H., & Jasin, M. (2011) · Cell · doi:10.1016/j.cell.2011.03.041 · Cited by 1,258 · cited 2× · see citing works
“HRR factors BRCA1 and BRCA2 have several specific functions and are recruited to prevent DNA degradation at stalled replication forks [86, 87], to promote the restart of replication and to drive HRR processes [88].”
Background
BRCAness revisited
Lord, C. J., & Ashworth, A. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2015.21 · Cited by 1,257 · see citing works
High-throughput sequencing of DNA G-quadruplex structures in the human genome
Chambers, V. S., Marsico, G., Boutell, J. M., Antonio, M. D., Smith, G. P., & Balasubramanian, S. (2015) · Nature Biotechnology · doi:10.1038/nbt.3295 · Cited by 1,238 · cited 1× · see citing works
“According to computational tools and genomic G4 mapping, G4s can occur across the genome, particularly enriched in gene regulatory regions and telomeres supporting fundamental functions [13, 14].”
Background
Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence
Glück, S., Guey, B., Gulen, M. F., Wolter, K., Kang, T.-W., Schmacke, N. A., Bridgeman, A., Rehwinkel, J., Zender, L., & Ablasser, A. (2017) · Nature Cell Biology · doi:10.1038/ncb3586 · Cited by 1,196 · see citing works
A tetrameric DNA structure with protonated cytosine-cytosine base pairs
Gehring, K., Leroy, J., & Guéron, M. (1993) · Nature · doi:10.1038/363561a0 · Cited by 1,069 · cited 1× · see citing works
“1C), through hemi-protonated cytosine-cytosine base pairing (C-C+) [57, 58], could stabilize the opposite C-rich DNA strand.”
Background
cGAS is essential for cellular senescence
Yang, H., Wang, H., Ren, J., Chen, Q., & Chen, Z. J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1705499114 · Cited by 1,009 · see citing works
G-quadruplex structures mark human regulatory chromatin
Hänsel-Hertsch, R., Beraldi, D., Lensing, S. V., Marsico, G., Zyner, K., Parry, A., Di Antonio, M., Pike, J., Kimura, H., Narita, M., et al. (2016) · Nature Genetics · doi:10.1038/ng.3662 · Cited by 964 · cited 2× · see citing works
“In addition, as nuclear levels of G4 structures can be higher in cancer than normal cells [14, 23, 24], published data converge on G4s as potentially-effective pharmacological targets for cancer treatment.”
Background
Prospects for combining targeted and conventional cancer therapy with immunotherapy
Gotwals, P. J., Cameron, S. B., Cipolletta, D., Cremasco, V., Crystal, A., Hewes, B., Mueller, B., Quaratino, S., Sabatos-Peyton, C. A., Petruzzelli, L., et al. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.17 · Cited by 948 · cited 1× · see citing works
“and topoisomerase‐mediated genome instability Immuno-modulation activity has been proposed also for Topoisomerase poisons arguing that immune-stimulation can contribute significantly to the therapeutic activity of established anticancer agents in patients [114, 115].”
Background
Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer
Sen, T., Rodriguez, B. L., Chen, L., Corte, C. M. D., Morikawa, N., Fujimoto, J., Cristea, S., Nguyen, T., Diao, L., Li, L., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1020 · Cited by 902 · cited 1× · see citing works
“In Small Cell Lung Cancer (SCLC) cell lines, only cells expressing STING and cGAS respond to a combination of Top1 poisons and PARP inhibitors with increased mRNA levels of Interferon-B gene [135].”
Background
Inhibition of Human Telomerase by a G-Quadruplex-Interactive Compound
Sun, D., Thompson, B., Cathers, B. E., Salazar, M., Kerwin, S. M., Trent, J. O., Jenkins, T. C., Neidle, S., & Hurley, L. H. (1997) · Journal of Medicinal Chemistry · doi:10.1021/jm970199z · Cited by 794 · cited 1× · see citing works
“Historically, G4 binders were designed to target telomeres with the aim to inhibit telomerase activity and consequently proliferation rate of immortalized cancer cells [44, 45].”
Background
R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells
Yu, K.-F., Chédin, F., Hsieh, C.-L., Wilson, T. E., & Lieber, M. (2003) · Nature Immunology · doi:10.1038/ni919 · Cited by 767 · cited 1× · see citing works
“They are key players in many biological processes such as replication, transcription activation and termination, and are crucial for immunoglobulin class-switch recombination (CSR) in activated B lymphocytes [66].”
Background
Catastrophic nuclear envelope collapse in cancer cell micronuclei
Hatch, E. M., Fischer, A. H., Deerinck, T. J., & Hetzer, M. W. (2013) · Cell · doi:10.1016/j.cell.2013.06.007 · Cited by 741 · see citing works
Small-molecule–induced DNA damage identifies alternative DNA structures in human genes
Rodriguez, R., Miller, K. M., Forment, J. V., Bradshaw, C. R., Nikan, M., Britton, S., Oelschlaegel, T., Xhemalce, B., Balasubramanian, S., & Jackson, S. P. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.780 · Cited by 741 · cited 2× · see citing works
“However, it is worth noting that, on the one hand, unrelated G4 binders have a different propensity to induce DNA cleavage in cancer cells [22] and on the other, DSBs are induced by G4 binders at non-cytotoxic dosage [19, 20, 89].”
Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways
Kraehenbuehl, L., Weng, C.-H., Eghbali, S., Wolchok, J., & Merghoub, T. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00552-7 · Cited by 731 · cited 1× · see citing works
“and autophagy in cancer cells The latest and successful progresses in medical oncology have been achieved by the development of effective anticancer immunotherapy [91, 92].”
Background
The Multifaceted Role of Chromosomal Instability in Cancer and Its Microenvironment
Bakhoum, S. F. W., & Cantley, L. C. (2018) · Cell · doi:10.1016/j.cell.2018.08.027 · Cited by 717 · cited 1× · see citing works
“These cellular processes have the potential of harnessing the innate immune system for cancer immunotherapy [43].”
Background
Non-canonical activation of the DNA sensing adaptor STING by ATM and IFI16 mediates NF-κB signaling after nuclear DNA damage
Dunphy, G., Flannery, S. M., Almine, J. F., Connolly, D. J., Paulus, C., Jønsson, K. L., Jakobsen, M. R., Nevels, M. M., Bowie, A. G., & Unterholzner, L. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.07.034 · Cited by 648 · cited 1× · see citing works
“In addition, STING is also involved in non-canonical cGAS-independent mechanisms [140].”
Background
RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer
Wolfe, A. L., Singh, K., Zhong, Y., Drewe, P., Rajasekhar, V. K., Sanghvi, V. R., Mavrakis, K. J., Jiang, M., Roderick, J. E., Van der Meulen, J., et al. (2014) · Nature · doi:10.1038/nature13485 · Cited by 635 · cited 2× · see citing works
“Emetine • Transcriptome-wide downregulation [34]”
Background
Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis
Xia, T., Konno, H., Ahn, J., & Barber, G. N. (2016) · Cell Reports · doi:10.1016/j.celrep.2015.12.029 · Cited by 589 · cited 1× · see citing works
“As STING gene promoter is often methylated in tumours, demethylating agents may increase STING expression and innate immune response upon induction of DNA damage by anticancer agents [132].”
Background
Transcription-Coupled Nucleotide Excision Repair Factors Promote R-Loop-Induced Genome Instability
Sollier, J., Stork, C. T., García-Rubio, M. L., Paulsen, R. D., Aguilera, A., & Cimprich, K. A. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.10.020 · Cited by 579 · cited 1× · see citing works
“Interestingly, unscheduled R-loop can be processed by transcription-coupled nucleotide excision repair (TC-NER) endonucleases XPF and XPG [126, 127].”
Background
CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours
Xu, H., Antonio, M. D., McKinney, S. E., Mathew, V., Ho, B., O’Neil, N. J., Santos, N. D., Silvester, J., Wei, V., Garcia, J., et al. (2017) · Nature Communications · doi:10.1038/ncomms14432 · Cited by 574 · cited 3× · see citing works
“Therefore, past research in the field focused on developing more cytotoxic ligands, some of which have shown antitumour activity in human tumour xenograft models, in particular in combination regimen or in homologous recombination (HR) repair-deficient tumours [25, 26].”
Background
DNA Replication through G-Quadruplex Motifs Is Promoted by the Saccharomyces cerevisiae Pif1 DNA Helicase
Paeschke, K., Capra, J. A., & Zakian, V. A. (2011) · Cell · doi:10.1016/j.cell.2011.04.015 · Cited by 566 · cited 1× · see citing works
“PIF1 gene depletion is also responsible for genetic and epigenetic G4-mediated changes [75, 76].”
Background
Rad51 protects nascent DNA from Mre11 dependent degradation and promotes continuous DNA synthesis
Hashimoto, Y., Chaudhuri, A., Lopes, M., & Costanzo, V. (2010) · Nature Structural &Molecular Biology · doi:10.1038/nsmb.1927 · Cited by 540 · cited 1× · see citing works
“HRR factors BRCA1 and BRCA2 have several specific functions and are recruited to prevent DNA degradation at stalled replication forks [86, 87], to promote the restart of replication and to drive HRR processes [88].”
Background
G-quadruplexes: a promising target for cancer therapy
Kosiol, N., Juranek, S., Brossart, P., Heine, A., & Paeschke, K. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01328-4 · Cited by 540 · cited 1× · see citing works
“Since the mutagenic burden of tumours correlates with the immunotherapeutic efficacy, G4 binder-mediated genome instability may even enhance tumour immunogenic responsiveness [105].”
Background
Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis.
Drygin, D., Siddiqui-Jain, A., O'Brien, S., Schwaebe, M., Lin, A., Bliesath, J., Ho, C., Proffitt, C., Trent, K., Whitten, J., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-1304 · Cited by 534 · cited 2× · see citing works
“CX-3543 (Quarfloxin) • Antitumor activity in mice [33]”
Background
Intracellular transcription of G-rich DNAs induces formation of G-loops, novel structures containing G4 DNA.Preprint
Duquette, M. L., Handa, P., Vincent, J. A., Taylor, A. F., & Maizels, N. (2004) · Genes & Development · doi:10.1101/gad.1200804 · Cited by 528 · cited 1× · see citing works
“Structural features that favour G4 folding (GC-richness, strand separation, negative supercoils) also favour the formation of R-loops, another non-B structure [20, 24, 63].”
Background
BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2
Bhatia, V., Barroso, S. I., García-Rubio, M. L., Tumini, E., Herrera‐Moyano, E., & Aguilera, A. (2014) · Nature · doi:10.1038/nature13374 · Cited by 527 · see citing works
I-motif DNA structures are formed in the nuclei of human cells
Zeraati, M., Langley, D., Schofield, P., Moye, A. L., Rouet, R., Hughes, W. E., Bryan, T., Dinger, M., & Christ, D. (2018) · Nature Chemistry · doi:10.1038/s41557-018-0046-3 · Cited by 475 · cited 1× · see citing works
“1C), through hemi-protonated cytosine-cytosine base pairing (C-C+) [57, 58], could stabilize the opposite C-rich DNA strand.”
Background
Pif1 family helicases suppress genome instability at G-quadruplex motifs
Paeschke, K., Bochman, M. L., Garcia, P. D., Ćejka, P., Friedman, K. L., Kowalczykowski, S. C., & Zakian, V. A. (2013) · Nature · doi:10.1038/nature12149 · Cited by 471 · cited 1× · see citing works
“PIF1 gene depletion is also responsible for genetic and epigenetic G4-mediated changes [75, 76].”
Background
Whole genome experimental maps of DNA G-quadruplexes in multiple species
Marsico, G., Chambers, V. S., Sahakyan, A. B., McCauley, P., Boutell, J. M., Antonio, M. D., & Balasubramanian, S. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz179 · Cited by 435 · cited 1× · see citing works
“Several genetic data further demonstrate the occurrence of G4 structures in the genome of humans and several other organisms, including bacteria and viruses [11, 12].”
Background
Loss of Topoisomerase I leads to R-loop-mediated transcriptional blocks during ribosomal RNA synthesis.Preprint
Hage, A. E., French, S., Beyer, A., & Tollervey, D. (2010) · Genes & Development · doi:10.1101/gad.573310 · Cited by 432 · cited 1× · see citing works
“Interestingly, Top1 has been shown to interact with G4 structures [119, 120] and to affect R-loop levels in cells [121, 122].”
Background
How long is too long? Effects of loop size on G-quadruplex stability
Guédin, A., Gros, J., Alberti, P., & Mergny, J. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq639 · Cited by 412 · cited 1× · see citing works
“A G-rich strand can fold into different G4 conformations depending on strand stoichiometry (intraor inter-strand topologies), strand direction (parallel, antiparallel or mixed) and length of intervening nucleotides (loops and bulges) [4, 5] (Fig.”
Background
Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands
Riou, J., Guittat, L., Mailliet, P., Laoui, A., Renou, E., Petitgenet, O., Mégnin-Chanet, F., Hélène, C., & Mergny, J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.052698099 · Cited by 395 · see citing works
The importance of negative superhelicity in inducing the formation of G-quadruplex and i-motif structures in the c-Myc promoter: implications for drug targeting and control of gene expression
Sun, D., & Hurley, L. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm900055s · Cited by 367 · cited 1× · see citing works
“Hurley and co-workers clearly established the importance of negative super-helicity for non-B structure folding at the c-MYC promoter [54, 55].”
Background
The Yeast Pif1 Helicase Prevents Genomic Instability Caused by G-Quadruplex-Forming CEB1 Sequences In Vivo
Ribeyre, C., Lopes, J., Boulé, J., Piazza, A., Guédin, A., Zakian, V., Mergny, J., & Nicolas, A. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000475 · Cited by 367 · cited 1× · see citing works
“cerevisiae by preventing replication-dependent DNA damage at G4 motifs [74].”
Background
Mre11-Dependent Degradation of Stalled DNA Replication Forks Is Prevented by BRCA2 and PARP1
Ying, S., Hamdy, F. C., & Helleday, T. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3417 · Cited by 346 · cited 1× · see citing works
“On the other hand, BRCA2 represses R-loop mediated replication stress by protecting replication fork from MRE11 degradation [86, 130].”
Background
DNA damage and genome instability by G-quadruplex ligands are mediated by R loops in human cancer cells
De Magis, A., Manzo, S. G., Russo, M., Marinello, J., Morigi, R., Sordet, O., & Capranico, G. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1810409116 · Cited by 332 · cited 10× · see citing works
“Interestingly, PDS and FG (Table 2) have been shown to promote R-loop-mediated micronuclei formation in human cancer cells and BRCA2 silencing increased micronuclei levels with respect to BRCA2 proficient cells [20].”
BackgroundInfluentialSelf-citation
DNA Damage and Cancer Immunotherapy: A STING in the Tale
Reisländer, T., Groelly, F. J., & Tarsounas, M. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.07.026 · Cited by 318 · cited 1× · see citing works
“Micronuclei are recognized by specific PRR or cytoplasmic DNA sensors like cGAS [98, 99], and cGAS bound to micronuclei leads to STING activation, which is a pivotal player in promoting Type I Interferon and other immune genes [100] as silencing, deletion or chemically inhibition of STING abolished immune genes respon…”
Background
DNA G-quadruplex structures: more than simple roadblocks to transcription?
Robinson, J., Raguseo, F., Nuccio, S. P., Liano, D., & Antonio, M. D. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab609 · Cited by 312 · see citing works
A G-Quadruplex-Interactive Potent Small-Molecule Inhibitor of Telomerase Exhibiting in Vitro and in Vivo Antitumor Activity
Gowan, S. M., Harrison, J. R., Patterson, L., Valenti, M. R., Read, M. A., Neidle, S., & Kèlland, L. R. (2002) · Molecular Pharmacology · doi:10.1124/mol.61.5.1154 · Cited by 305 · cited 1× · see citing works
“Historically, G4 binders were designed to target telomeres with the aim to inhibit telomerase activity and consequently proliferation rate of immortalized cancer cells [44, 45].”
Background
DNA-Containing Exosomes Derived from Cancer Cells Treated with Topotecan Activate a STING-Dependent Pathway and Reinforce Antitumor Immunity
Kitai, Y., Kawasaki, T., Sueyoshi, T., Kobiyama, K., Ishii, K., Zou, J., Akira, S., Matsuda, T., & Kawai, T. (2017) · Journal of Immunology · doi:10.4049/jimmunol.1601694 · Cited by 296 · cited 1× · see citing works
“Interestingly, Topotecan, a clinically used Top1 poison, can activate dendritic cells of tumour-bearing mice as exosomes released by the treated tumours are incorporated by dendritic cells, which then triggers the cGAS/STING signalling pathway [136].”
Background
Chemotherapeutics and Radiation Stimulate MHC Class I Expression through Elevated Interferon-beta Signaling in Breast Cancer Cells
Wan, S., Pestka, S., Jubin, R. G., Lyu, Y. L., Tsai, Y.-C., & Liu, L. F. (2012) · PLoS ONE · doi:10.1371/journal.pone.0032542 · Cited by 295 · cited 1× · see citing works
“Combination of Top1 poisons with immunotherapies is further supported by evidence that in breast cancer cells Topotecan induces IFN I signalling and upregulation of class I MHC genes [133], a potential mechanism for immune sensitization of tumours deficient of MHC antigens on membrane surface.”
Background
Nucleic Acid Immunity
Hartmann, G. (2017) · Advances in Immunology · doi:10.1016/bs.ai.2016.11.001 · Cited by 285 · cited 3× · see citing works
“Interestingly, the activity of G4 binders can activate a physiological process, known as Pathogen- or Damage-Associated Molecular Patterns (PAMPs or DAMPs), activated mainly in immune cells by microbial or viral infections through the activity of Pattern Recognition Receptors (PRR) [97].”
Background
Targeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting Compounds
Zimmer, J., Tacconi, E. M. C., Folio, C., Badie, S., Porru, M., Klare, K., Tumiati, M., Markkanen, E., Halder, S., Ryan, A., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2015.12.004 · Cited by 261 · cited 3× · see citing works
“Therefore, past research in the field focused on developing more cytotoxic ligands, some of which have shown antitumour activity in human tumour xenograft models, in particular in combination regimen or in homologous recombination (HR) repair-deficient tumours [25, 26].”
Background
PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells
Quinet, A., Tirman, S., Jackson, J., Šviković, S., Lemacon, D. S., Carvajal-Maldonado, D., González‐Acosta, D., Vessoni, A. T., Cybulla, E., Wood, M. D., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.10.008 · Cited by 259 · see citing works
G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3′ telomeric overhang in cancer cells
Tahara, H., Shin‐ya, K., Seimiya, H., Yamada, H., TSURUO, T., & Ide, T. (2005) · Oncogene · doi:10.1038/sj.onc.1209217 · Cited by 238 · see citing works
Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives
Marinello, J., Delcuratolo, M., & Capranico, G. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113480 · Cited by 234 · cited 1× · see citing works
“and topoisomerase‐mediated genome instability Immuno-modulation activity has been proposed also for Topoisomerase poisons arguing that immune-stimulation can contribute significantly to the therapeutic activity of established anticancer agents in patients [114, 115].”
BackgroundSelf-citation
Interactions between the Werner Syndrome Helicase and DNA Polymerase δ Specifically Facilitate Copying of Tetraplex and Hairpin Structures of the d(CGG) n Trinucleotide Repeat Sequence*
Kamath-Loeb, A., Loeb, L., Johansson, E., Burgers, P., & Fry, M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100253200 · Cited by 227 · see citing works
Genome-wide mapping of G-quadruplex structures with CUT&Tag
Lyu, J., Shao, R., Yung, P. Y. K., & Elsässer, S. J. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab1073 · Cited by 225 · see citing works
G-quadruplex, Friend or Foe: The Role of the G-quartet in Anticancer Strategies.
Carvalho, J., Mergny, J., Salgado, G., Queiroz, J., & Cruz, C. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.05.002 · Cited by 224 · see citing works
Elevated Levels of G-Quadruplex Formation in Human Stomach and Liver Cancer Tissues
Biffi, G., Tannahill, D., Miller, J., Howat, W. J., & Balasubramanian, S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0102711 · Cited by 223 · see citing works
Transcriptome-wide identification of transient RNA G-quadruplexes in human cells
Yang, S. Y. C., Lejault, P., Chevrier, S., Boidot, R., Robertson, A. G., Wong, J. M. Y., & Monchaud, D. (2018) · Nature Communications · doi:10.1038/s41467-018-07224-8 · Cited by 218 · cited 3× · see citing works
“RHPS4 • Telomere targeting • Apoptosis • Transcriptional landscape alterations • B-cell proliferation arrest [32, 38]”
Background
Mutagenic Capacity of Endogenous G4 DNA Underlies Genome Instability in FANCJ-Defective C. elegans
Kruisselbrink, E., Guryev, V., Brouwer, K., Pontier, D. B., Cuppen, E., & Tijsterman, M. (2008) · Current Biology · doi:10.1016/j.cub.2008.05.013 · Cited by 209 · cited 1× · see citing works
“elegans as a DOG1 (FANCJ) gene deletion could lead to accumulation of small deletions upstream to putative G4s [73].”
Background
Permanganate/S1 nuclease footprinting reveals non-B DNA structures with regulatory potential across a mammalian genome
Kouzine, F., Wójtowicz, D., Baranello, L., Yamane, A., Nelson, S., Resch, W., Kieffer-Kwon, K.-R., Benham, C., Casellas, R., Przytycka, T., et al. (2017) · Cell Systems · doi:10.1016/j.cels.2017.01.013 · Cited by 202 · cited 2× · see citing works
“G4s are highly dynamic structures and their steady-state levels are generally low in nuclei of unperturbed living cells [52].”
Background
Thermodynamic and kinetic characterization of the dissociation and assembly of quadruplex nucleic acids
Hardin, C. C., Perry, A. G., & White, K. (2000) · Biopolymers · doi:10.1002/1097-0282(2000/2001)56:3 · Cited by 202 · see citing works
Optimized end-stacking provides specificity of N-methyl mesoporphyrin IX for human telomeric G-quadruplex DNA.
Nicoludis, J. M., Miller, S. T., Jeffrey, P., Barrett, S. P., Rablen, P. R., Lawton, T. J., & Yatsunyk, L. (2012) · Journal of the American Chemical Society · doi:10.1021/ja3088746 · Cited by 199
Autophagic removal of micronuclei
Rello-Varona, S., Lissa, D., Shen, S., Niso-Santano, M., Senovilla, L., Mariño, G., Vitale, I., Jemaá, M., Harper, F., Pierron, G., et al. (2012) · Cell Cycle · doi:10.4161/cc.11.1.18564 · Cited by 198 · cited 1× · see citing works
“Moreover, as autophagy is involved in micronuclei clearance [111], the functional effect of autophagy needs to be fully understood in relation to the potential role of G4 binders as immunomodulators of antitumour immunity.”
Background
Homologous recombination restarts blocked replication forks at the expense of genome rearrangements by template exchange.
Lambert, S., Mizuno, K., Blaisonneau, J., Martineau, S., Chanet, R., Fréon, K., Murray, J., Carr, A., & Baldacci, G. (2010) · Molecules and Cells · doi:10.1016/j.molcel.2010.07.015 · Cited by 197 · cited 1× · see citing works
“HRR factors BRCA1 and BRCA2 have several specific functions and are recruited to prevent DNA degradation at stalled replication forks [86, 87], to promote the restart of replication and to drive HRR processes [88].”
Background
Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors
Arora, S., Velichinskii, R. A., Lesh, R. W., Ali, U., Kubiak, M. J., Bansal, P., Borghaei, H., Edelman, M. J., & Boumber, Y. (2019) · Advances in Therapy · doi:10.1007/s12325-019-01051-z · Cited by 197 · cited 1× · see citing works
“In this scenario, the action of non-cytotoxic G4 binder doses may play a further role to promote an immune-therapeutic activity as immunotherapy efficacy is strictly related to the mutational burden of tumours [103, 104].”
Background
Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy
Bartsch, K., Knittler, K., Borowski, C., Rudnik, S., Damme, M., Aden, K., Spehlmann, M. E., Frey, N., Saftig, P., Chalaris, A., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx283 · Cited by 196 · cited 3× · see citing works
“The excess of micronuclei in AGS cells also stimulates autophagy, which in turn targets micronuclei for lysosomal degradation, therefore preventing further stimulation of the innate immune response [110].”
BackgroundInfluential
Nascent connections: R-loops and chromatin patterning
Chédin, F. (2016) · Trends in Genetics · doi:10.1016/j.tig.2016.10.002 · Cited by 196 · cited 1× · see citing works
“R-loop formation is a dynamic event at active genes, and they can cover 4–7% of a cell genome [65].”
Background
The cGAS/STING Pathway: A Novel Target for Cancer Therapy
Gan, Y., Li, X., Han, S., Liang, Q., Ma, X., Rong, P., Wang, W., & Li, W. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.795401 · Cited by 190 · cited 1× · see citing works
“The role of STING in cancer progression and treatment is therefore more complex as it exhibits both tumour-suppressive and tumour-promoting effects [142, 143].”
Background
Visualising G-quadruplex DNA dynamics in live cells by fluorescence lifetime imaging microscopy
Summers, P. A., Lewis, B. W., González‐García, J., Porreca, R. M., Lim, A. H. M., Cadinu, P., Martín‐Pintado, N., Mann, D. J., Edel, J. B., Vannier, J., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20414-7 · Cited by 188 · see citing works
G-quadruplex unwinding helicases and their function <i>in vivo</i>
Sauer, M., & Paeschke, K. (2017) · Biochemical Society Transactions · doi:10.1042/bst20170097 · Cited by 179 · see citing works
Stabilization of quadruplex DNA perturbs telomere replication leading to the activation of an ATR-dependent ATM signaling pathway
Rizzo, A., Salvati, E., Porru, M., D’Angelo, C., Stevens, M. F. G., D’Incalci, M., Leonetti, C., Gilson, É., Zupi, G., & Biroccio, A. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp582 · Cited by 176 · see citing works
Insight into the Complexity of the i-Motif and G-Quadruplex DNA Structures Formed in the KRAS Promoter and Subsequent Drug-Induced Gene Repression
Kaiser, C. E., Ert, N. A. V., Agrawal, P., Chawla, R., Yang, D., & Hurley, L. H. (2017) · Journal of the American Chemical Society · doi:10.1021/jacs.7b02046 · Cited by 176 · cited 1× · see citing works
“As transcription elongation is the main source of torsional stress and unwinding of the genome, G4 folding at transcribed genes can then be regulated by the stabilization of the opposite DNA strand by either protein factors or other secondary structures [56].”
Background
Dual Processing of R-Loops and Topoisomerase I Induces Transcription-Dependent DNA Double-Strand Breaks
Cristini, A., Ricci, G., Britton, S., Salimbeni, S., Huang, S.-Y. N., Marinello, J., Calsou, P., Pommier, Y. G., Favre, G., Capranico, G., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.041 · Cited by 171 · cited 1× · see citing works
“Interestingly, unscheduled R-loop can be processed by transcription-coupled nucleotide excision repair (TC-NER) endonucleases XPF and XPG [126, 127].”
BackgroundSelf-citation
Targeting Multiple Effector Pathways in Pancreatic Ductal Adenocarcinoma with a G-Quadruplex-Binding Small Molecule
Marchetti, C., Zyner, K. G., Ohnmacht, S. A., Robson, M. P., Haider, S. M., Morton, J. P., Marsico, G., Vo, T. D., Laughlin, S., Ahmed, A. A., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01781 · Cited by 166 · cited 3× · see citing works
“AQ1 • Oncogene targeting • Oncogenic cell death • Cell survival inhibition [30, 31]”
Background
The dynamic response of upstream DNA to transcription-generated torsional stress
Kouzine, F., Liu, J.-H., Sanford, S., Chung, H.-J., & Levens, D. (2004) · Nature Structural &Molecular Biology · doi:10.1038/nsmb848 · Cited by 165 · cited 1× · see citing works
“When DNA is not replicating, the transition of DNA from canonical B-form to G4s or alternative secondary structures likely requires strand unwinding of the double helix by local negative DNA supercoils [52, 53].”
Background
PrimPol Is Required for Replicative Tolerance of G Quadruplexes in Vertebrate Cells
Schiavone, D., Jozwiakowski, S. K., Romanello, M., Guilbaud, G., Guilliam, T. A., Bailey, L. J., Sale, J., & Doherty, A. (2016) · Molecules and Cells · doi:10.1016/j.molcel.2015.10.038 · Cited by 164 · cited 1× · see citing works
“Therefore, PrimPol activity allows the restart of fork progression bypassing the structural obstacle and prevents genomic instability [80].”
Background
BLM helicase facilitates telomere replication during leading strand synthesis of telomeres
Drosopoulos, W. C., Kosiyatrakul, S. T., & Schildkraut, C. L. (2015) · The Journal of Cell Biology · doi:10.1083/jcb.201410061 · Cited by 164 · cited 2× · see citing works
“In particular, replication forks using a telomeric G-rich strand template proceed slower than adjacent non G-rich DNAs and fork progression is further slowed down in the presence of a G4 binder [70].”
Background
Stabilization of G-quadruplex DNA, inhibition of telomerase activity, and tumor cell apoptosis by organoplatinum(II) complexes with oxoisoaporphine.
Chen, Z.-F., Qin, Q.-P., Qin, J.-L., Liu, Y.-C., Huang, K.-B., Li, Y.-L., Meng, T., Zhang, G.-H., Peng, Y., Luo, X.-J., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/jm5012484 · Cited by 156 · cited 2× · see citing works
“Pt1 • Telomerase inhibition • Cancer cells apoptosis [37]”
Background
Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease
Sharma, M., Rajendrarao, S., Shahani, N., Ramírez-Jarquín, U. N., & Subramaniam, S. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2002144117 · Cited by 155 · cited 1× · see citing works
“This is consistent with other findings showing that the cGAS-STING pathway activates the autophagy process through a TANK-binding kinase 1 (TBK1) independent mechanism [108] and that cGAS is a critical regulator of inflammation and autophagy in Huntington’s disease [109].”
Result
Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies
Hilton, J., Gelmon, K., Bedard, P. L., Tu, D., Xu, H., Tinker, A. V., Goodwin, R., Laurie, S. A., Jonker, D., Hansen, A. R., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31199-2 · Cited by 155 · cited 3× · see citing works
“NCT02719977 CX-5461 (Pidnarulex) Phase 1 Cancer Active, not recruiting / [27] Canada 2016”
BackgroundInfluential
BRCA2 Regulates Transcription Elongation by RNA Polymerase II to Prevent R-Loop Accumulation
Shivji, M. K., Renaudin, X., Williams, C. H., & Venkitaraman, A. (2018) · Cell Reports · doi:10.1016/j.celrep.2017.12.086 · Cited by 150 · cited 3× · see citing works
“Moreover, BRCA2 gene inactivation can cause site-specific formation of unscheduled R-loops and a ERCC4 endonuclease-mediated DNA breaks [129].”
Background
DNA Topoisomerase I differentially modulates R-loops across the human genome
Manzo, S. G., Hartono, S. R., Sanz, L. A., Marinello, J., Biasi, S. D., Cossarizza, A., Capranico, G., & Chédin, F. (2018) · Genome Biology · doi:10.1186/s13059-018-1478-1 · Cited by 140 · cited 2× · see citing works
“As Top 1 can directly bind G4 structures in vitro [119, 120], it may have an important role in controlling R-loop and its cellular depletion results into a G1/S transition block [122, 124].”
BackgroundSelf-citation
G-quadruplex–R-loop interactions and the mechanism of anticancer G-quadruplex binders
Miglietta, G., Russo, M. V., & Capranico, G. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa944 · Cited by 135 · cited 6× · see citing works
“Unbalanced levels of R-loops cause RNA polymerase pausing impairing gene transcription [22, 125].”
BackgroundInfluentialSelf-citation
Mutagenic consequences of a single G-quadruplex demonstrate mitotic inheritance of DNA replication fork barriers
Lemmens, B., van Schendel, R., & Tijsterman, M. (2015) · Nature Communications · doi:10.1038/ncomms9909 · Cited by 133 · cited 1× · see citing works
“The singlestrand gap then becomes double-strand break (DSB) during S-phase of daughter cells, which can eventually repair DSB by alternative Polθ-end joining pathway [83], causing an increase of genome instability.”
Background
R-loop induced G-quadruplex in non-template promotes transcription by successive R-loop formation
Lee, C.-Y., McNerney, C., Ma, K., Zhao, W., Wang, A., & Myong, S. (2020) · Nature Communications · doi:10.1038/s41467-020-17176-7 · Cited by 128 · cited 2× · see citing works
“In particular, a G4 in the template strand inhibits RNA polymerase elongation, whereas a G4 in the non-template strand affects transcription depending on the specific genomic and chromatin context [50].”
Background
G-quadruplex DNA structures in human stem cells and differentiation
Zyner, K. G., Simeone, A., Flynn, S. M., Doyle, C., Marsico, G., Adhikari, S., Portella, G., Tannahill, D., & Balasubramanian, S. (2022) · Nature Communications · doi:10.1038/s41467-021-27719-1 · Cited by 122 · cited 3× · see citing works
“Notably, the authors found that G4 stabilization mediated by PhenDC3 at not cytotoxic concentration causes delayed differentiation of hESC due to failure of pluripotency exit [36].”
Background
Interaction of human DNA topoisomerase I with G-quartet structures.
Arimondo, P. B., Riou, J.-F., Mergny, J., Tazi, J., Sun, J.-S., Garestier, T., & Hélène, C. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.24.4832 · Cited by 117 · cited 3× · see citing works
“Therefore, alterations of homeostatic G-loop dynamics may also be caused by impairment of Top1 interactions with G4 functions [119, 120].”
Background
Mutation-Derived Neoantigens for Cancer Immunotherapy
Castle, J. C., Uduman, M., Pabla, S. S., Stein, R. B., & Buell, J. S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01856 · Cited by 115 · cited 1× · see citing works
“In this scenario, the action of non-cytotoxic G4 binder doses may play a further role to promote an immune-therapeutic activity as immunotherapy efficacy is strictly related to the mutational burden of tumours [103, 104].”
Background
A Mechanosensor Mechanism Controls the G-Quadruplex/i-Motif Molecular Switch in the MYC Promoter NHE III1.
Sutherland, C., Cui, Y.-X., Mao, H., & Hurley, L. (2016) · Journal of the American Chemical Society · doi:10.1021/jacs.6b09196 · Cited by 114 · cited 2×
“However, single-molecule studies showed a mutual exclusivity between i-motifs and G4s at the Myc promoter [59] and other gene promoters [60, 61].”
Background
G-quadruplex and i-motif are mutually exclusive in ILPR double-stranded DNA.
Dhakal, S., Yu, Z., Konik, R., Cui, Y.-X., Koirala, D., & Mao, H. (2012) · Biophysical Journal · doi:10.1016/j.bpj.2012.04.024 · Cited by 111 · cited 1×
“However, single-molecule studies showed a mutual exclusivity between i-motifs and G4s at the Myc promoter [59] and other gene promoters [60, 61].”
Background
DNA G-Quadruplex and i-Motif Structure Formation Is Interdependent in Human Cells.
King, J. J., Irving, K. L., Evans, C. W., Chikhale, R., Becker, R., Morris, C., Martinez, C. D. P., Schofield, P., Christ, D., Hurley, L., et al. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c11708 · Cited by 108 · cited 1×
“In addition, chemical G4 stabilization has been shown to destabilize i-motifs in cultured cells, and vice versa [62], suggesting an interplay of G4 and i-motif formation in relation to DNA function regulations in human cells [59, 62].”
Background
N‐methylmesoporphyrin IX fluorescence as a reporter of strand orientation in guanine quadruplexes
Sabharwal, N. C., Savikhin, V., Turek-Herman, J., Nicoludis, J. M., Szalai, V., & Yatsunyk, L. (2014) · The FEBS Journal · doi:10.1111/febs.12734 · Cited by 108
Mutually Exclusive Formation of G-Quadruplex and i-Motif Is a General Phenomenon Governed by Steric Hindrance in Duplex DNA.
Cui, Y.-X., Kong, D.-M., Ghimire, C., Xu, C.-X., & Mao, H. (2016) · Biochemistry · doi:10.1021/acs.biochem.6b00016 · Cited by 104 · cited 2×
“As simultaneous formation of the G4s and i-motifs in opposite strands occurs only when they are placed in an offset fashion [61], the mutual exclusivity is likely due to steric hindrance of the two structures.”
Background
R‐loop formation during S phase is restricted by PrimPol‐mediated repriming
Šviković, S., Crisp, A., Tan‐Wong, S. M., Guilliam, T. A., Doherty, A. J., Proudfoot, N. J., Guilbaud, G., & Sale, J. E. (2018) · The EMBO Journal · doi:10.15252/embj.201899793 · Cited by 101 · see citing works
A novel K(+)-dependent DNA synthesis arrest site in a commonly occurring sequence motif in eukaryotes.
Woodford, K., Howell, R., & Usdin, K. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)47121-9 · Cited by 100 · see citing works
The Effect of Topoisomerase I Inhibitors on the Efficacy of T-Cell-Based Cancer Immunotherapy
McKenzie, J. A., Mbofung, R. M., Malu, S., Zhang, M., Ashkin, E. L., Devi, S., Williams, L. J., Tieu, T. N., Peng, W., Pradeep, S., et al. (2017) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djx257 · Cited by 91 · cited 1× · see citing works
“In a set of melanoma models, Top1 poisons have been shown to increase T-cell-mediated cytotoxicity in cells expressing TP53 [134].”
Background
Dynamic DNA binding, junction recognition and G4 melting activity underlie the telomeric and genome-wide roles of human CST
Bhattacharjee, A., Wang, Y.-Y., Diao, J.-J., & Price, C. M. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx878 · Cited by 90 · cited 1× · see citing works
“In particular, STN1 localization is altered after treatment with different G4 binders suggesting that G4 stabilization triggers the CST complex redistribution at specific genome sites to reduce G4 accumulation and to allow replication process [78, 79].”
Background
Viral G-quadruplexes: New frontiers in virus pathogenesis and antiviral therapy
Ruggiero, E., & Richter, S. (2020) · Annual Reports in Medicinal Chemistry · doi:10.1016/bs.armc.2020.04.001 · Cited by 89 · cited 1×
“Several genetic data further demonstrate the occurrence of G4 structures in the genome of humans and several other organisms, including bacteria and viruses [11, 12].”
Background
TET deficiency perturbs mature B cell homeostasis and promotes oncogenesis associated with accumulation of G-quadruplex and R-loop structures
Shukla, V., Samaniego‐Castruita, D., Dong, Z., González‐Avalos, E., Yan, Q., Sarma, K., & Rao, A. (2021) · Nature Immunology · doi:10.1038/s41590-021-01087-w · Cited by 88 · cited 2× · see citing works
“Structural features that favour G4 folding (GC-richness, strand separation, negative supercoils) also favour the formation of R-loops, another non-B structure [20, 24, 63].”
Background
Multistep mechanism of G-quadruplex resolution during DNA replication
Sato, K., Martin-Pintado, N., Post, H., Altelaar, M., & Knipscheer, P. (2021) · Science Advances · doi:10.1126/sciadv.abf8653 · Cited by 80 · cited 1× · see citing works
“A coordinated action of three helicases, DHX35, FANCJ and the replicative CMG complex, has recently been shown to promote bypass and unfolding of stabilized G4s during replication in an ex-vivo model of Xenopus egg extracts [77].”
Background
Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons
Moruno-Manchon, J. F., Lejault, P., Wang, Y., McCauley, B. S., Honarpisheh, P., Morales‐Scheihing, D., Singh, S. S., Dang, W., Kim, N., Urayama, A., et al. (2020) · eLife · doi:10.7554/elife.52283 · Cited by 80 · cited 5× · see citing works
“Interestingly, the two studied G4 binders showed a different strength in autophagy downregulation [113], suggesting a role for ligand-specific patterns of stabilized G4s or activation of different ligand-specific processes.”
BackgroundInfluential
Antisense transcripts enhanced by camptothecin at divergent CpG-island promoters associated with bursts of topoisomerase I-DNA cleavage complex and R-loop formation
Marinello, J., Chillemi, G., Bueno, S., Manzo, S. G., & Capranico, G. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt778 · Cited by 79 · see citing works
Self-citation
Mammalian CST averts replication failure by preventing G-quadruplex accumulation
Zhang, M., Wang, B., Li, T., Liu, R., Xiao, Y., Geng, X., Li, G., Liu, Q., Price, C. M., Liu, Y., et al. (2018) · bioRxiv · doi:10.1093/nar/gkz264 · Cited by 78 · cited 1× · see citing works
“In particular, STN1 localization is altered after treatment with different G4 binders suggesting that G4 stabilization triggers the CST complex redistribution at specific genome sites to reduce G4 accumulation and to allow replication process [78, 79].”
Background
Strong transcription blockage mediated by R-loop formation within a G-rich homopurine–homopyrimidine sequence localized in the vicinity of the promoter
Belotserkovskii, B. P., Shin, J. H. S., & Hanawalt, P. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx403 · Cited by 78 · cited 1× · see citing works
“Unbalanced levels of R-loops cause RNA polymerase pausing impairing gene transcription [22, 125].”
Background
G4LDB 2.2: a database for discovering and studying G-quadruplex and i-Motif ligands
Wang, Y.-H., Yang, Q.-F., Lin, X., Chen, D., Wang, Z.-Y., Chen, B., Han, H., Chen, H., Cai, K., Li, Q., et al. (2021) · Nucleic Acids Res. · doi:10.1093/nar/gkab952 · Cited by 74 · cited 1× · see citing works
“The diversity of this class of molecules is high (> 3000 compounds) [48], including also metal-containing compounds (as the organoplatinum complex Pt1, Table 2) with cell killing potential and ability to induce cell senescence [37, 49].”
Background
Modulation of the ATM/autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells
Beauvarlet, J., Bensadoun, P., Darbo, E., Labrunie, G., Rousseau, B., Richard, E., Draskovic, I., Londono-Vallejo, A., Dupuy, J.-W., Nath Das, R., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz095 · Cited by 73 · cited 2× · see citing works
“The study presents the ATM/autophagy axis as a key player for cell fate between senescence and apoptosis, therefore suggesting that autophagy can be a target to induce G4 ligand-dependent cancer cell death [28].”
Background
Template-directed pausing in in vitro DNA synthesis by DNA polymerase a from Drosophila melanogaster embryos.
Kaguni, L. S., & Clayton, D. A. (1982) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.79.4.983 · Cited by 73 · see citing works
G-quadruplex binders as cytostatic modulators of innate immune genes in cancer cells
Miglietta, G., Russo, M. V., Duardo, R. C., & Capranico, G. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab500 · Cited by 72 · cited 10× · see citing works
“Recent findings showed that chemically-unrelated G4 binders are able to induce micronuclei accumulation in different cancer cell lines [35, 89], indicating that micronuclei induction is a common effect of many G4 binders.”
BackgroundMethodInfluentialSelf-citation
The Evolution of STING Signaling and Its Involvement in Cancer
Vashi, N., & Bakhoum, S. F. W. (2021) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2020.12.010 · Cited by 70 · cited 1× · see citing works
“The role of STING in cancer progression and treatment is therefore more complex as it exhibits both tumour-suppressive and tumour-promoting effects [142, 143].”
Background
The role of G-quadruplex/i-motif secondary structures as cis-acting regulatory elements
Kendrick, S., & Hurley, L. (2010) · Pure and applied chemistry. Chimie pure et appliquee · doi:10.1351/pac-con-09-09-29 · Cited by 69 · cited 1× · see citing works
“Hurley and co-workers clearly established the importance of negative super-helicity for non-B structure folding at the c-MYC promoter [54, 55].”
Background
Interaction of Human Nuclear Topoisomerase I with Guanosine Quartet-forming and Guanosine-rich Single-stranded DNA and RNA Oligonucleotides*
Marchand, C., Pourquier, P., Laco, G., Jing, N., & Pommier, Y. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m106372200 · Cited by 62 · cited 3×
“Therefore, alterations of homeostatic G-loop dynamics may also be caused by impairment of Top1 interactions with G4 functions [119, 120].”
Background
G-quadruplex ligand SYUIQ-5 induces autophagy by telomere damage and TRF2 delocalization in cancer cells
Zhou, W.-J., Deng, R., Zhang, X.-Y., Feng, G., Gu, L., & Zhu, X. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0244 · Cited by 60 · cited 1× · see citing works
“In contrast, SYUIQ-5 (Table 2) has been shown to promote telomeric DNA damage by TRF2 delocalization and an ATMdependent autophagic cell death [39].”
Background
G4-Interacting DNA Helicases and Polymerases: Potential Therapeutic Targets
Estep, K. N., Butler, T. J., Ding, J., & Brosh, R. M. (2019) · Current Medicinal Chemistry · doi:10.2174/0929867324666171116123345 · Cited by 58 · see citing works
Autophagy acts as a safeguard mechanism against G-quadruplex ligand-mediated DNA damage
Orlotti, N. I., Cimino-Reale, G., Borghini, E., Pennati, M., Sissi, C., Perrone, F., Palumbo, M., Daidone, M. G., Folini, M., & Zaffaroni, N. (2012) · Autophagy · doi:10.4161/auto.20519 · Cited by 56 · see citing works
Topoisomerase I poison-triggered immune gene activation is markedly reduced in human small-cell lung cancers by impairment of the cGAS/STING pathway
Marinello, J., Arleo, A., Russo, M. V., Delcuratolo, M., Ciccarelli, F. D., Pommier, Y. G., & Capranico, G. (2022) · British Journal of Cancer · doi:10.1038/s41416-022-01894-4 · Cited by 55 · cited 14× · see citing works
“CPT-induced micronuclei lead to the cGAS/STING pathway activation at later times following cell recovery in drug-free medium, then increasing the expression of innate immune genes [118].”
BackgroundInfluentialSelf-citation
G4 DNA in ras genes and its potential in cancer therapy
Cogoi, S., & Xodo, L. E. (2016) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2016.02.002 · Cited by 51 · cited 1× · see citing works
“This strategy may be a solution for undruggable proteins, such as RAS in RAS-driven tumours [16].”
Background
Guanine repeat-containing sequences confer transcription-dependent instability in an orientation-specific manner in yeast
Kim, N., & Jinks-Robertson, S. (2011) · DNA Repair · doi:10.1016/j.dnarep.2011.07.002 · Cited by 51 · cited 2× · see citing works
“Top 1 deletion resulted into chromosomal aberrations of Sμ regions through R-loop accumulation [123].”
Background
Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses
Pépin, G., Nejad, C., Ferrand, J., Thomas, B. J., Stunden, H. J., Sanij, E., Foo, C. H., Stewart, C. R., Cain, J. E., Bardin, P. G., et al. (2017) · mBio · doi:10.1128/mbio.01611-17 · Cited by 49 · cited 1× · see citing works
“Consistently, other published data have shown stimulation of anti-viral immune pathways by Top1 poisons [131].”
Background
Rad51 and DNA-PKcs are involved in the generation of specific telomere aberrations induced by the quadruplex ligand 360A that impair mitotic cell progression and lead to cell death
Gauthier, L., Granotier-Beckers, C., Hoffschir, F., Etienne, O., Ayouaz, A., Desmaze, C., Mailliet, P., Biard, D. S. F., & Boussin, F. D. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0767-6 · Cited by 47 · see citing works
STING protects breast cancer cells from intrinsic and genotoxic-induced DNA instability via a non-canonical, cell-autonomous pathway
Cheradame, L., Guerrera, I. C., Gaston, J., Schmitt, A., Jung, V. A., Goudin, N., Pouillard, M., Radosevic‐Robin, N., Modesti, M., Judde, J., et al. (2021) · Oncogene · doi:10.1038/s41388-021-02037-4 · Cited by 47 · see citing works
The role of topoisomerase I in suppressing genome instability associated with a highly transcribed guanine-rich sequence is not restricted to preventing RNA:DNA hybrid accumulation
Yadav, P., Owiti, N. A., & Kim, N. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1152 · Cited by 46 · cited 1× · see citing works
“As Top 1 can directly bind G4 structures in vitro [119, 120], it may have an important role in controlling R-loop and its cellular depletion results into a G1/S transition block [122, 124].”
Background
Monohydrazone Based G-Quadruplex Selective Ligands Induce DNA Damage and Genome Instability in Human Cancer Cells
Amato, J., Miglietta, G., Morigi, R., Iaccarino, N., Locatelli, A., Leoni, A., Novellino, E., Pagano, B., Capranico, G., & Randazzo, A. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01866 · Cited by 44 · cited 3× · see citing works
“Recent findings showed that chemically-unrelated G4 binders are able to induce micronuclei accumulation in different cancer cell lines [35, 89], indicating that micronuclei induction is a common effect of many G4 binders.”
BackgroundSelf-citation
Metal-Based G-Quadruplex Binders for Cancer Theranostics
Palma, E., Carvalho, J., Cruz, C., & Paulo, A. (2021) · Pharmaceuticals · doi:10.3390/ph14070605 · Cited by 44 · cited 1× · see citing works
“The diversity of this class of molecules is high (> 3000 compounds) [48], including also metal-containing compounds (as the organoplatinum complex Pt1, Table 2) with cell killing potential and ability to induce cell senescence [37, 49].”
Background
Rethinking Alkylating(-Like) Agents for Solid Tumor Management.
Lajous, H., Lelièvre, B., Vauléon, E., Lecomte, P., & Garcion, E. (2019) · TIPS - Trends in Pharmacological Sciences · doi:10.1016/j.tips.2019.03.003 · Cited by 41 · cited 1× · see citing works
“nucleophilic groups in cells, effectively lowering their nuclear concentrations [41].”
Background
Regulation of autophagy by DNA G-quadruplexes
Lejault, P., Moruno-Manchon, J. F., Vemu, S. M., Honarpisheh, P., Zhu, L., Kim, N., Urayama, A., Monchaud, D., McCullough, L. D., & Tsvetkov, A. S. (2020) · Autophagy · doi:10.1080/15548627.2020.1769991 · Cited by 31 · cited 2× · see citing works
“In addition, G4 binder treatments led to memory loss or defects, and to accelerated ageing of treated mice [112, 113].”
Background
Whole-Transcriptome Profiling of Canine and Human in Vitro Models Exposed to a G-Quadruplex Binding Small Molecule
Zorzan, E., Elgendy, R., Giantin, M., Dacasto, M., & Sissi, C. (2018) · Scientific Reports · doi:10.1038/s41598-018-35516-y · Cited by 19 · cited 3×
“AQ1 • Oncogene targeting • Oncogenic cell death • Cell survival inhibition [30, 31]”
Background
Monomeric G-Quadruplex-Based CpG Oligodeoxynucleotides as Potent Toll-Like Receptor 9 Agonists.
Tu, A. T. T., Hoshi, K., Ikebukuro, K., Hanagata, N., & Yamazaki, T. (2020) · Biomacromolecules · doi:10.1021/acs.biomac.0c00679 · Cited by 18 · cited 3× · see citing works
“Interestingly, the activity of G4 binders can activate a physiological process, known as Pathogen- or Damage-Associated Molecular Patterns (PAMPs or DAMPs), activated mainly in immune cells by microbial or viral infections through the activity of Pattern Recognition Receptors (PRR) [97].”
Background
G-quadruplex DNA targeting alters class-switch recombination in B cells and attenuates allergic inflammation.
Dalloul, Z., Chenuet, P., Dalloul, I., Boyer, F., Aldigier, J., Laffleur, B., Makhour, Y. E., Ryffel, B., Quesniaux, V., Togbe, D., et al. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2018.06.011 · Cited by 18 · cited 8×
“Interestingly, low doses (sub-cytotoxic) of RHPS4 (Table 2) directly target CSR of immunoglobulin genes in B cells, while neither decreasing B-cell growth nor triggering apoptosis.”
BackgroundInfluential
Transcription-associated DNA breaks and cancer: A matter of DNA topology.
Cristini, A., Geraud, M., & Sordet, O. (2021) · International Review of Cell and Molecular Biology · doi:10.1016/bs.ircmb.2021.05.001 · Cited by 11 · see citing works
Effects of G-Quadruplex Ligands on the Topology, Stability, and Immunostimulatory Properties of G-Quadruplex-Based CpG Oligodeoxynucleotides.
Tu, A. T. T., Hoshi, K., Ma, Y., Oyama, T., Suzuki, S., Tsukakoshi, K., Nagasawa, K., Ikebukuro, K., & Yamazaki, T. (2022) · ACS Chemical Biology · doi:10.1021/acschembio.1c00904 · Cited by 8 · cited 2×
“tested ligands to stabilize and maintain the hybrid quadruplex topology [107].”
Background

Flagged first, then by citations

1 of the 145 references couldn’t be matched to a known paper.

Sorted by citations

G-quadruplex ligands in cancer therapy: Progress, challenges, and clinical perspectives
Figueiredo, J., Mergny, J., & Cruz, C. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.122481 · Cited by 142 · see citing works
Non-B DNA structures as a booster of genome instability
Duardo, R. C., Guerra, F., Pepe, S., & Capranico, G. (2023) · Biochimie · doi:10.1016/j.biochi.2023.07.002 · Cited by 48 · see citing works
Self-citation
Spotlight on G-Quadruplexes: From Structure and Modulation to Physiological and Pathological Roles
dell’Oca, M. C., Quadri, R., Bernini, G. M., Menin, L., Grasso, L., Rondelli, D., Yazici, O., Sertic, S., Marini, F., Pellicioli, A., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063162 · Cited by 29 · see citing works
“Despite the growth in characterized G-quadruplex binders and the increased cytotoxicity of newer compounds, few have entered phase I clinical trials owing to their limited potency [341].”
BackgroundInfluential
G-Quadruplexes in Human Telomere: Structures, Properties, and Applications
Xu, Y., & Komiyama, M. (2023) · Molecules · doi:10.3390/molecules29010174 · Cited by 28 · see citing works
G-quadruplex-mediated genomic instability drives SNVs in cancer
Richl, T., Kuper, J., & Kisker, C. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae098 · Cited by 20 · see citing works
“However, G4s hold various regulatory functions in transcription and translation ( 20 ), deregulated or ligand-induced G4-formation is associated with the activation of DNA-damage responses, implying that aberrant G4-formation triggers similar pathways as DNA-damage ( 83 ).”
Background
Novel phenanthrene imidazoles as telomeric G-quadruplex ligands trigger potent immunogenic cell death in triple-negative breast cancer.
Wang, X., Wang, J.-X., & Hu, M.-H. (2023) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2023.126068 · Cited by 16 · see citing works
G-quadruplex ligands as potent regulators of lysosomes
Ferret, L., Alvarez-Valadez, K., Rivière, J., Muller, A., Bohálová, N., Yu, L., Guittat, L., Brázda, V., Kroemer, G., Mergny, J., et al. (2023) · Autophagy · doi:10.1080/15548627.2023.2170071 · Cited by 15 · see citing works
Promising G-Quadruplex-Targeted Dibenzoquinoxaline Type-1 Photosensitizer Triggers DNA Damage in Triple-Negative Breast Cancer Cells
Zhang, X., Wang, J., & Hu, M.-H. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00234 · Cited by 19 · see citing works
G-quadruplex-guided cisplatin triggers multiple pathways in targeted chemotherapy and immunotherapy
Ma, T., Liu, L., Zeng, Y., Ding, K., Zhang, H., Liu, W., Cao, Q., Xia, W. T., Xiong, X., Wu, C., et al. (2024) · Chemical Science · doi:10.1039/d4sc00643g · Cited by 31 · see citing works
“10,11 Therefore, G4 receives great attention as a potentially e ﬀ ective pharmacological target for cancer therapy and provides a great opportunity for drug design towards a new cancer strategy.”
The Intertwined Role of 8-oxodG and G4 in Transcription Regulation
Gorini, F., Ambrosio, S., Lania, L., Majello, B., & Amente, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032031 · Cited by 14 · see citing works
Facilitating Quantitation of Mitochondrial G-Quadruplex DNA with an Iridium(III) Two-Photon Phosphorescence Lifetime Imaging Probe.
Xiong, K., Ouyang, C., Wang, F., Wen, Y., Wu, X.-B., Liang, J., Chen, Y., Leung, C.-H., & Chao, H. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c17409 · Cited by 13
DNA G-quadruplexes: Structural and functional insights
Jonchhe, S., Lahiri, S., & Rothenberg, E. (2025) · DNA repair · doi:10.1016/j.dnarep.2025.103910 · Cited by 12 · see citing works
Stimulation of cGAS-STING pathway as a challenge in the treatment of small cell lung cancer: a feasible strategy?
Miglietta, G., Russo, M. V., Capranico, G., & Marinello, J. (2024) · British Journal of Cancer · doi:10.1038/s41416-024-02821-5 · Cited by 12 · see citing works
“Cytoplasmatic DNA is a key point to stimulate an innate immune response in cancers cells and, as recently demonstrated, micronuclei are stimulated by a plethora of drugs and compounds, including molecules that target DNA non-canonical structures like G-quadruplexes (G4) [83 – 85].”
BackgroundSelf-citation
Discovery of a tribenzophenazine analog for binding to the KRAS mRNA G-quadruplex structures in the cisplatin-resistant non–small cell lung cancer
Wang, X.-D., Lin, J.-H., & Hu, M.-H. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.108164 · Cited by 12 · see citing works
Solution structures and effects of a platinum compound successively bound MYC G-quadruplex
Liu, W.-T., Zhu, B., Liu, L.-Y., Xia, X., Jang, J., Dickerhoff, J., Yang, D.-Z., & Mao, Z.-W. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae649 · Cited by 11 · see citing works
Cell redistribution of G quadruplex‐structured DNA is associated with morphological changes of nuclei and nucleoli in neurons during tau pathology progression
Comptdaer, T., Tardivel, M., Schirmer, C., Buée, L., & Galas, M. (2024) · Brain Pathology · doi:10.1111/bpa.13262 · Cited by 8 · see citing works
“Interestingly, in cancer and noncancer cells, G4 binders which stabilize G4 structures can stimulate innate immunity [80].”
Conversion to Trimolecular G-Quadruplex by Spontaneous Hoogsteen Pairing-Based Strand Displacement Reaction between Bimolecular G-Quadruplex and Double G-Rich Probes.
Hu, W., Jing, H.-T., Fu, W.-Z., Wang, Z., Zhou, J., & Zhang, N. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c05617 · Cited by 7 · see citing works
Expression of down-regulated ERV LTR elements associates with immune activation in human small-cell lung cancers
Russo, M., Morelli, S., & Capranico, G. (2023) · Mobile DNA · doi:10.1186/s13100-023-00290-w · Cited by 7 · see citing works
“DDR inhibitors or DNA-interacting agents can increase the surface expression of PD-L1 and/or activate the cGAS-STING pathway, mediated by cytosolic DNA sensors, leading to Type I interferon stimulated gene (ISG) expression [6, 7] and tumour-infiltrating cytotoxic T-lymphocytes [5, 8].”
BackgroundSelf-citation
G-quadruplex stabilization via small molecules as a potential anti-cancer strategy
Li, C., Liu, J., & Wang, R. (2026) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-026-00890-3 · Cited by 6 · see citing works
“Capranico and colleagues reported that G4 ligands can trigger the cGAS–STING pathway, leading to type I interferon and ISG signaling [167, 168].”
Genomic context influences translesion synthesis DNA polymerase-dependent mechanisms of micronuclei induction by G-quadruplexes
Pepe, S., Guerra, F., Russo, M., Duardo, R. C., & Capranico, G. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115706 · Cited by 7 · see citing works
Self-citation
Telomeric repeat-containing RNA G-quadruplexes trigger ZBP1-mediated cell death
Qin, G., Zhao, C.-Q., Gao, C.-M., Hu, W., Zhang, N., Ren, J.-S., & Qu, X.-G. (2026) · Nature Communications · doi:10.1038/s41467-026-69989-7 · Cited by 5 · see citing works
Molecular Tools for Precision Targeting and Detection of G-Quadruplex Structures
Esposito, D., Locatelli, A., & Morigi, R. (2025) · Molecules · doi:10.3390/molecules30204099 · Cited by 5 · see citing works
“…by the fact that prokaryotic and eukaryotic cells are equipped with a robust system of specialized helicases that effectively unfold G4s during DNA replication, allowing an effective fork progression, such as Pif1 in S. cerevisiae [33,34] and Bloom helicase (BLM) in mammalian cells [35,36].”
Immunoregulatory kinases and T-cell pathways in DNA-damage response and autoimmune inflammation: Emerging roles of BUB1 and IGFL2
Bukke, S. P. N., Chettupalli, A. K., Sharma, C. B., Thalluri, C., Eftekhari, Z., & Yadesa, T. M. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.116509 · Cited by 4 · see citing works
La3+ and Dy3+ hexaaza macrocycles revisited: Enhanced stabilization of G-quadruplex DNA-spectroscopic and in silico studies.
Ewert, E., Marcinkowski, D., Pospieszna-Markiewicz, I., Palumbo, R., Hnatejko, Z., Kubicki, M., Gorczyński, A., Wieczorek-Szweda, E., Patroniak, V., Roviello, G., et al. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.148269 · Cited by 3
Rationalizing the structural basis of organic-platinum hybrid complexes binding towards quadruplex-duplex hybrids through all-atom simulations.
Muscarella, S., Treccarichi, I., D'Anna, L., & Spinello, A. (2025) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2025.112904 · Cited by 3 · see citing works
Structural Diversity and Mechanistic Insights on Preferential Interaction of Small Molecule Ligands with i‐Motif DNA Structures: Unlocking New Blueprint for Drug Discovery
Bag, S., Ghosal, S., Burman, M. D., Manna, A., & Bhowmik, S. (2025) · ChemistrySelect · doi:10.1002/slct.202501985 · Cited by 2
Targeting DHODH promoter G-quadruplex to induce ferroptosis in melanoma cells.
Zhang, W., Xu, Q., & Sui, Y. (2025) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2025.153117 · Cited by 1
Archaeal G-quadruplexes: a novel model for understanding unusual DNA/RNA structures across the tree of life
Aktary, Z., Sorg, K., Cucchiarini, A., Vesco, G., Noury, D., Zhang, R., Jourdain, T., Verga, D., Mahou, P., Olivier, N., et al. (2025) · bioRxiv · doi:10.1093/nar/gkag067 · Cited by 1
“Numerous G4-stabilizing ligands (G4 ligands or G4L) have been identified, and some are under investigation for their therapeutic potential [ 18 , 39 –41 ].”
The interactions of 9-methoxyluminarine with Bcl-2 G-quadruplex
Nowak-Karnowska, J., Głuszyńska, A., Kosman, J., Haider, S., & Dembska, A. (2025) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2025.143531 · Cited by 1
Impact of imidazolium-based ionic liquid, functionalized with aromatic compounds, on thermophysical and aggregation properties
Pereira, V. S., Beck, T. S., Zibetti, L., Santos, B. S. C., Moraes, A. C., Bender, C., Villetti, M., & Frizzo, C. (2025) · Journal of Molecular Liquids · doi:10.1016/j.molliq.2025.127579 · Cited by 1
G-quadruplex structures affect the immune response to bacterial infection in mouse macrophages
Schult, P., Kastl, M. A., Szlapa, J., Symeonidis, K., Maasewerd, S., Franklin, B., Radcke, A., Juranek, S., Abdullah, Z., & Paeschke, K. (2026) · Nature Communications · doi:10.1038/s41467-026-78610-w
Regulation of Tumor-Immune Cell Communications via Enantioselectively Targeting SLC G-Quadruplexes.
Sun, Y., Yuan, H., Song, H., Zhao, C.-Q., Postings, M. L., Scott, P., Hu, W., Zhang, N., Ren, J.-S., & Qu, X.-G. (2026) · Journal of the American Chemical Society · doi:10.1021/jacs.6c07127
Exploration of multifunctional characteristics and regulatory mechanism of promoter G-quadruplexes.
Zhao, Z.-Y., Zhang, Y.-Z., Tian, J.-J., Su, Y., Lin, S., Chen, K., Zhu, L.-J., & Xu, W.-T. (2026) · Pharmacological Reviews · doi:10.1016/j.pharmr.2026.100151
G4 Ligands and Their Interaction Diversity with G-Quadruplex
Vashistha, V. K., Mittal, A., Upadhyay, P. K., Nagar, H., Kumar, R., Gupta, H., Bala, R., & Das, D. K. (2023) · Russian journal of bioorganic chemistry · doi:10.1134/s1068162023030238

Authors: Miglietta, G., Marinello, J., Russo, M., & Capranico, G.
Affiliations: University of Bologna (IT)
Corresponding author: Capranico, Giovanni
ORCID: Miglietta, Giulia
Marinello, Jessica
Russo, Marco
Capranico, Giovanni
Venue: Molecular Cancer
Publisher: Springer Science and Business Media LLC
Published: 2022-09-17
Volume: 21
Issue: 1
Pages: 180-180
ISSN: 1476-4598 (ISSN-L)
DOI: 10.1186/s12943-022-01649-y
PMC: PMC9482198
OpenAlex: W4296162137
Cited by: 44
References: 145
Citations by year: 2026: 7 · 2025: 13 · 2024: 12 · 2023: 10 · 2022: 2
FWCI: 0.96
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Molecular Cancer (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Associazione Italiana per la Ricerca sul Cancro (23953, IG-2019, 23032)
Fondazione Italiana per la Ricerca sul Cancro (23953)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
Keywords: G-quadruplex binders, antitumor immunity, low-dose drug effects, genomic instability, autophagy, innate immune response, anticancer drug discovery
MeSH terms: Antineoplastic Agents, Humans, Ligands, Neoplasms, Genomic Instability, G-Quadruplexes

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Ligands stimulating antitumour immunity as the next G-quadruplex challenge

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Record

About these checks