Transcription-associated topoisomerase 2α (TOP2A) activity is a major effector of cytotoxicity induced by G-quadruplex ligands
Open accessAbstract
G-quadruplexes (G4) are non-canonical DNA structures found in the genome of most species including human. Small molecules stabilizing these structures, called G4 ligands, have been identified and, for some of them, shown to induce cytotoxic DNA double-strand breaks. Through the use of an unbiased genetic approach, we identify here topoisomerase 2α (TOP2A) as a major effector of cytotoxicity induced by two clastogenic G4 ligands, pyridostatin and CX-5461, the latter molecule currently undergoing phase I/II clinical trials in oncology. We show that both TOP2 activity and transcription account for DNA break production following G4 ligand treatments. In contrast, clastogenic activity of these G4 ligands is countered by topoisomerase 1 (TOP1), which limits co-transcriptional G4 formation, and by factors promoting transcriptional elongation. Altogether our results support that clastogenic G4 ligands act as DNA structure-driven TOP2 poisons at transcribed regions bearing G4 structures.
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Recent genome-wide investigations underscore that these effects are not confined to promotors, but are rather observed across the genome.
“Recent genome-wide investigations underscore that these effects are not confined to promotors, but are rather observed across the genome (68–70).”
From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [70]
The Introduction (page unavailable) says G-quadruplexes are present throughout the human genome and reports genome-wide associations with RNA polymerase pausing and R-loop-forming regions. The paper also describes G4-ligand effects at transcribed genomic regions, but the passages do not establish that those effects were observed across the genome rather than at promoters alone. (LLM, conf=0.78)
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26 S Proteasome-mediated Degradation of Topoisomerase II Cleavable Complexes
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MethodSelf-citationTopoisomerase-mediated chromosomal break repair: an emerging player in many games
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BackgroundResultG-Quadruplex DNA as a Molecular Target for Induced Synthetic Lethality in Cancer Cells
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“…BRD4 and TOP1 activities as well as the reduction of RNA-Pol elongation has been shown to promote R-loops (Shivji et al., 2018; Tuduri et al., 2009; Zhang et al., 2017; Kim et al., 2019; El Hage et al., 2010; Li et al., 2015), a DNA-RNA secondary structure associated with the formation of…”
BackgroundLam, F. C., Kong, Y. W., Huang, Q., Vu‐Han, T., Maffa, A., Kasper, E. M., & Yaffe, M. B. (2020) · Nature Communications · doi:10.1038/s41467-020-17503-y · Cited by 154 · see citing works
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 5× · see citing works
“Interestingly, the inhibition of BRD4 and TOP1 activities as well as the reduction of RNA-Pol elongation has been shown to promote R-loops (Shivji et al., 2018; Tuduri et al., 2009; Zhang et al., 2017; Kim et al., 2019; El Hage et al., 2010; Li et al., 2015), a DNA-RNA secondary structure associated with the formation…”
BackgroundInfluentialNakamura, K. M., Kogame, T., Oshiumi, H., Shinohara, A., Sumitomo, Y., Agama, K., Pommier, Y. G., Tsutsui, K., Tsutsui, K., Hartsuiker, E., et al. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1000828 · Cited by 149 · see citing works
Gothe, H. J., Bouwman, B. A. M., Gusmao, E. G., Piccinno, R., Petrosino, G., Sayols, S., Drechsel, O., Minneker, V., Josipović, N., Mizi, A., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.05.015 · Cited by 147 · see citing works
A Protease Pathway for the Repair of Topoisomerase II-DNA Covalent Complexes
Zhang, A., Lyu, Y. L., Lin, C., Zhou, N., Azarova, A. M., Wood, L. M., & Liu, L. F. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604149200 · Cited by 146 · cited 2× · see citing works
“Moreover, genome-wide analysis of TOP2A cleavage sites shows a significant enrichment of TOP2A on highly transcribed loci (Zhang et al., 2006).”
BackgroundThe Interplay between G-quadruplex and Transcription
Kim, N. (2017) · Current Medicinal Chemistry · doi:10.2174/0929867325666171229132619 · Cited by 146 · cited 1× · see citing works
“In addition, increasing evidence also indicates a significant impact of G4 structures on genomic stability through transcription-dependent processes (Kotsantis et al., 2020; Miglietta et al., 2020; De Magis et al., 2019; Rodriguez et al., 2012; van Wietmarschen et al., 2018; Kim, 2019).”
BackgroundCarpenter, A. J., & Porter, A. C. G. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-08-0732 · Cited by 139 · see citing works
Kim, J. J., Lee, S. Y., Gong, F., Battenhouse, A. M., Boutz, D. R., Bashyal, A., Refvik, S. T., Chiang, C., Xhemalçe, B., Paull, T. T., et al. (2019) · Genes & Development · doi:10.1101/gad.331231.119 · Cited by 139 · cited 7× · see citing works
“Interestingly, the inhibition of BRD4 and TOP1 activities as well as the reduction of RNA-Pol elongation has been shown to promote R-loops (Shivji et al., 2018; Tuduri et al., 2009; Zhang et al., 2017; Kim et al., 2019; El Hage et al., 2010; Li et al., 2015), a DNA-RNA secondary structure associated with the formation…”
BackgroundInfluentialDNA Topoisomerase II as a Target for Cancer Chemotherapy
Walker, J. V., & Nitiss, J. L. (2002) · Cancer Investigation · doi:10.1081/cnv-120002156 · Cited by 138 · see citing works
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 · see citing works
Lentiviral vectors: optimization of packaging, transduction and gene expression
Delenda, C. (2004) · The Journal of Gene Medicine · doi:10.1002/jgm.501 · Cited by 133 · cited 2× · see citing works
“Transfection of HEK-293T cells (kindly provided by Genethon, Evry, France) with pLV-tTR-KRAB-Red or pLVTHM, and preparation of high titer lentiviruses pseudotyped with VSV-G protein have been performed as previously described (Delenda, 2004).”
MethodMRN, CtIP, and BRCA1 mediate repair of topoisomerase II–DNA adducts
Aparicio, T., Baer, R. J., Gottesman, M. E., & Gautier, J. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201504005 · Cited by 123 · cited 1× · see citing works
“…protein from DNA through TOP2 proteolysis (Fan et al., 2008; Mao et al., 2001; Zhang et al., 2006) or nucleolytic degradation of the associated DNA (Aparicio et al., 2016; Nakamura et al., 2010) and the repair of the resulting DSB by non-homologous end joining (NHEJ) (Gómez-Herreros et al., 2013)…”
BackgroundDNA topoisomerase IIα is required for RNA polymerase II transcription on chromatin templates
Mondal, N., & Parvin, J. (2001) · Nature · doi:10.1038/35096590 · Cited by 121 · see citing works
G4 motifs correlate with promoter-proximal transcriptional pausing in human genes
Eddy, J., Vallur, A. C., Varma, S., Liu, H., Reinhold, W. C., Pommier, Y. G., & Maizels, N. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr079 · Cited by 121 · cited 1× · see citing works
“transcription-dependent DNA breaks (Puget et al., 2019; Chen et al., 2017; Eddy et al., 2011).”
DrugTargetSeqR: a genomics- and CRISPR-Cas9–based method to analyze drug targets
Kasap, C., Elemento, O., & Kapoor, T. M. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1551 · Cited by 119 · cited 1× · see citing works
“In addition, CXR clones did not show cross-resistance to the unrelated drug and efflux-pumps substrate nocodazole (Kasap et al., 2014), excluding a multidrug resistance (MDR) phenotype (Supplementary file 1).”
BackgroundBLM helicase suppresses recombination at G-quadruplex motifs in transcribed genes
van Wietmarschen, N., Merzouk, S., Halsema, N., Spierings, D. C. J., Guryev, V., & Lansdorp, P. M. (2018) · Nature Communications · doi:10.1038/s41467-017-02760-1 · Cited by 118 · see citing works
G-quadruplex dynamics contribute to regulation of mitochondrial gene expression
Falabella, M., Kolesar, J. E., Wallace, C. T., de Jesus, D. S., Sun, L., Taguchi, Y. V., Wang, C., Wang, T., Xiang, I. M., Alder, J. K., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-41464-y · Cited by 113 · cited 2× · see citing works
“For instance, the main impact of RHPS4 on mitochondrial DNA is related to its ability to translocate to the mitochondria, which is most probably due to its positive charge (Falabella et al., 2019).”
BackgroundAustin, C. A., Lee, K. C., Swan, R. L., Khazeem, M. M., Manville, C. M., Cridland, P., Treumann, A., Porter, A., Morris, N. J., & Cowell, I. G. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19092765 · Cited by 100 · cited 1× · see citing works
“The main role of TOP2A in producing transcription-associated DNA breaks in response to PDS is at first intriguing since TOP2B is considered as the principal TOP2 responsible for the resolution of topological stress associated with transcription (Pommier et al., 2016; Nitiss, 2009a; Madabhushi, 2018; Austin et al., 201…”
BackgroundA nucleotide resolution map of Top2-linked DNA breaks in the yeast and human genome
Gittens, W. H., Johnson, D., Allison, R. M., Cooper, T. J., Thomas, H., & Neale, M. J. (2019) · Nature Communications · doi:10.1038/s41467-019-12802-5 · Cited by 99 · see citing works
Cleavage of cellular DNA by calicheamicin γ1
Elmroth, K. (2003) · DNA repair · doi:10.1016/s1568-7864(02)00235-5 · Cited by 96 · cited 1× · see citing works
“Since camptothecin induces toxic replication-associated DSBs, which are mainly repaired by HR, while calicheamicin induces DSB in all cell cycle phases, which are repaired by both NHEJ and HR (Elmroth et al., 2003; Furuta et al., 2003), these results indicate that DSB repair mechanisms are proficient in TOP2A mutated…”
Akimitsu, N., Adachi, N., Hirai, H., Hossain, M. S., Hamamoto, H., Kobayashi, M., Aratani, Y., Koyama, H., & Sekimizu, K. (2003) · Genes to Cells · doi:10.1046/j.1365-2443.2003.00643.x · Cited by 94 · cited 3× · see citing works
“Immunoblotting analysis revealed that none of the identified TOP2A mutations resulted in the loss of TOP2A protein, in agreement with its essential function in proliferating cells (Akimitsu et al., 2003; Carpenter and Porter, 2004).”
BackgroundPuget, N., Miller, K. M., & Legube, G. (2019) · DNA repair · doi:10.1016/j.dnarep.2019.102661 · Cited by 90 · see citing works
Small Molecule BMH-Compounds That Inhibit RNA Polymerase I and Cause Nucleolar Stress
Peltonen, K., Colis, L. C., Liu, H., Jäämaa, S., Zhang, Z., af Hällström, T., Moore, H. M., Sirajuddin, P., & Laiho, M. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0256 · Cited by 90 · cited 2× · see citing works
“BHM21, a DNA intercalator showing a preferential binding to GC-rich sequences (Peltonen et al., 2014) but not to G4 structures (Xu et al.”
BackgroundFroelich-Ammon, S. J., Gale, K. C., & Osheroff, N. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)37346-5 · Cited by 87 · see citing works
CNBP controls transcription by unfolding DNA G-quadruplex structures
David, A. P., Pipier, A., Pascutti, F., Binolfi, A., Weiner, A. M. J., Challier, E., Heckel, S., Calsou, P., Gómez, D., Calcaterra, N. B., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz527 · Cited by 80 · see citing works
Self-citationEmerging roles for R-loop structures in the management of topological stress
Chédin, F., & Benham, C. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.rev119.006364 · Cited by 77 · see citing works
Mars, J.-C., Tremblay, M. G., Valere, M., Sibai, D. S., Sabourin‐Félix, M., Lessard, F., & Moss, T. (2020) · NAR Cancer · doi:10.1093/narcan/zcaa032 · Cited by 76 · cited 2× · see citing works
“Although the cytotoxic effects induced by this compound have been related to rDNA-transcription inhibition (Mars et al., 2020; Negi and Brown, 2015), CX-5461 has also been shown to be a potent G4 stabilizer and to provoke rapid induction of DSBs through a TOP2-dependent mechanism (Bruno et al.,…”
BackgroundTammaro, M., Barr, P., Ricci, B., & Yan, H. (2013) · PLoS ONE · doi:10.1371/journal.pone.0079202 · Cited by 75 · cited 1× · see citing works
“, 2017) and its activity is required for maximal production of transcription-dependent DNA breaks induced by ETP, a potent poison of TOP2 (Tammaro et al., 2013).”
BackgroundNG6: Integrated next generation sequencing storage and processing environment
Mariette, J., Escudié, F., Allias, N., Salin, G., Noirot, C., Thomas, S., & Klopp, C. (2012) · BMC Genomics · doi:10.1186/1471-2164-13-462 · Cited by 70 · cited 1× · see citing works
“…using a paired-end read length of 2 150 bp. RNA-seq alignment and SNP prediction and filtering Read quality was checked within the ng6 environment (Mariette et al., 2012) using fastQC (http:// www.bioinformatics.babraham.ac.uk/projects/fastqc/) and Burrows-Wheeler Aligner (BWA) (Li and Durbin,…”
MethodSelf-citationShen, W., Sun, H., Hoyos, C. L. D., Bailey, J., Liang, X., & Crooke, S. T. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx710 · Cited by 68 · cited 5× · see citing works
“In human cells, CX-5461 and PDS have been shown to provoke a rapid accumulation of R-loops (De Magis et al., 2019; Sanij et al., 2020; Shen et al., 2017; Duquette et al., 2004), which have been associated with the production of transcription-dependent DSBs and genomic instability (De Magis et al.”
BackgroundInfluentialThe Roles of DNA Topoisomerase IIβ in Transcription
Madabhushi, R. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19071917 · Cited by 67 · cited 4× · see citing works
“TOP2A plays key roles in DNA replication and chromosome segregation, while TOP2B is mainly associated with transcription (Pommier et al., 2016; Nitiss, 2009a; Madabhushi, 2018).”
BackgroundInfluentialRay, S., Panova, T. B., Miller, G., Volkov, A., Porter, A. C. G., Russell, J., Panov, K. I., & Zomerdijk, J. C. B. M. (2013) · Nature Communications · doi:10.1038/ncomms2599 · Cited by 64 · cited 2× · see citing works
“However, some studies also implicate TOP2A in transcription (Mondal and Parvin, 2001; Ray et al., 2013; Yu et al., 2017) and its activity is required for maximal production of transcription-dependent DNA breaks induced by ETP, a potent poison of TOP2 (Tammaro et al., 2013).”
BackgroundYadav, P., Harcy, V., Argueso, J. L., Dominska, M., Jinks-Robertson, S., & Kim, N. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004839 · Cited by 64 · cited 2× · see citing works
“Consistent with our data, TOP1 depletion in yeast drives genomic instability at highly transcribed G4-forming sequences (Yadav et al., 2014; Yadav et al., 2016).”
BackgroundCellular processing pathways contribute to the activation of etoposide-induced DNA damage responses
Fan, J.-R., Peng, A., Chen, H.-C., Lo, S.-C., Huang, T. H., & Li, T. (2008) · DNA repair · doi:10.1016/j.dnarep.2007.12.002 · Cited by 63 · see citing works
Li, M., Pokharel, S., Wang, J.-T., Xu, X., & Liu, Y. (2015) · Nature Communications · doi:10.1038/ncomms7720 · Cited by 62 · cited 6× · see citing works
“…elongation has been shown to promote R-loops (Shivji et al., 2018; Tuduri et al., 2009; Zhang et al., 2017; Kim et al., 2019; El Hage et al., 2010; Li et al., 2015), a DNA-RNA secondary structure associated with the formation of transcription-dependent DNA breaks (Aguilera, 2002; Gaillard et al.,…”
BackgroundInfluentialRTEL1 Regulates G4/R-Loops to Avert Replication-Transcription Collisions
Kotsantis, P., Segura‐Bayona, S., Margalef, P., Marzec, P., Ruis, P., Hewitt, G., Bellelli, R., Patel, H., Goldstone, R. J., Poetsch, A. R., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108546 · Cited by 60 · see citing works
Transcription-Associated Genome Instability
Gaillard, H., Herrera‐Moyano, E., & Aguilera, A. (2013) · Chemical Reviews · doi:10.1021/cr400017y · Cited by 59 · cited 2× · see citing works
“, 2015), a DNA-RNA secondary structure associated with the formation of transcription-dependent DNA breaks (Aguilera, 2002; Gaillard et al., 2013; GómezGonzález and Aguilera, 2019; Aguilera and Garcı́a-Muse, 2012).”
BackgroundJonstrup, A. T., Thomsen, T., Wang, Y., Knudsen, B. R., Koch, J., & Andersen, A. H. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn640 · Cited by 56 · see citing works
Genome-wide TOP2A DNA cleavage is biased toward translocated and highly transcribed lociPreprint
Yu, X., Davenport, J. W., Urtishak, K. A., Carillo, M. L., Gosai, S. J., Kolaris, C. P., Byl, J. A. W., Rappaport, E. F., Osheroff, N., Gregory, B. D., et al. (2017) · Genome Research · doi:10.1101/gr.211615.116 · Cited by 56 · cited 1× · see citing works
“However, some studies also implicate TOP2A in transcription (Mondal and Parvin, 2001; Ray et al., 2013; Yu et al., 2017) and its activity is required for maximal production of transcription-dependent DNA breaks induced by ETP, a potent poison of TOP2 (Tammaro et al., 2013).”
BackgroundThe effects of DNA supercoiling on G-quadruplex formation
Sekibo, D. A. T., & Fox, K. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx856 · Cited by 55 · see citing works
Identification of a Small-Molecule Inhibitor of DNA Topoisomerase II by Proteomic Profiling
Kawatani, M., Takayama, H., Muroi, M., Kimura, S. H., Maekawa, T., & Osada, H. (2011) · Chemistry & Biology · doi:10.1016/j.chembiol.2011.03.012 · Cited by 51 · see citing works
Induction of apoptosis by deregulated expression of DNA topoisomerase IIalpha.
McPherson, J. P., & Goldenberg, G. J. (1998) · PubMed · Cited by 48 · see citing works
Yadav, P., Owiti, N. A., & Kim, N. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1152 · Cited by 46 · cited 2× · see citing works
“Consistent with our data, TOP1 depletion in yeast drives genomic instability at highly transcribed G4-forming sequences (Yadav et al., 2014; Yadav et al., 2016).”
BackgroundBisquinolinium compounds induce quadruplex-specific transcriptome changes in HeLa S3 cell lines
Halder, R., Riou, J., Teulade-Fichou, M., Frickey, T., & Hartig, J. (2012) · BMC Research Notes · doi:10.1186/1756-0500-5-138 · Cited by 46 · cited 2× · see citing works
“…both telomere maintenance and mitochondrial DNA replication (Falabella et al., 2019; Salvati et al., 2007), while two selective bisquinolinium G4 ligands, 360A and PhenDC3, impact on telomeres, gene expression, and RNA metabolism (Dumas et al., 2021; Halder et al., 2012; Pennarun et al., 2005).”
BackgroundSelf-citationThe Top1 paradox: Friend and foe of the eukaryotic genome
Kim, N., & Jinks-Robertson, S. (2017) · DNA repair · doi:10.1016/j.dnarep.2017.06.005 · Cited by 42 · cited 1× · see citing works
“In cells, topological stresses induced by transcription are mainly resolved by the TOP1 protein (Kim and Jinks-Robertson, 2017).”
BackgroundZheng, K., He, Y.-D., Liu, H., Li, X., Hao, Y., & Tan, Z. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.7b00435 · Cited by 42 · cited 2× · see citing works
“Interestingly, elevated transcription levels have been shown to promote G4 formation that are favored by negative superhelicity caused by the progression of RNA-Pol complexes through DNA (Zheng et al., 2017).”
BackgroundTopoisomerase II contributes to DNA secondary structure-mediated double-stranded breaks
Szlachta, K. A., Manukyan, A., Raimer, H. M., Singh, S., Salamon, A., Guo, W., Lobachev, K. S., & Wang, Y. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa483 · Cited by 42 · see citing works
Genome-wide genetic screening with chemically mutagenized haploid embryonic stem cells
Forment, J. V., Herzog, M., Coates, J., Konopka, T., Gapp, B. V., Nijman, S. M., Adams, D. J., Keane, T. M., & Jackson, S. P. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2226 · Cited by 40 · cited 2× · see citing works
“To do this, human near haploid HAP1 cells were randomly mutagenized with ethyl methane sulfonate (EMS) based on previous work (Forment et al., 2017) and clones resistant to a lethal CX-5461 concentration of 0.”
MethodHuman DNA topoisomerase IIbeta binds and cleaves four-way junction DNA in vitro
West, K. L. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.4.984 · Cited by 39 · see citing works
Negi, S., & Brown, P. A. (2015) · Oncotarget · doi:10.18632/oncotarget.5413 · Cited by 30 · cited 2× · see citing works
“Although the cytotoxic effects induced by this compound have been related to rDNA-transcription inhibition (Mars et al., 2020; Negi and Brown, 2015), CX-5461 has also been shown to be a potent G4 stabilizer and to provoke rapid induction of DSBs through a TOP2-dependent mechanism (Bruno et al.,…”
BackgroundDNA:RNA hybrid G-quadruplex formation upstream of transcription start site
Zhang, J., Xia, Y., Hao, Y., & Tan, Z. (2020) · Scientific Reports · doi:10.1038/s41598-020-64117-x · Cited by 25 · cited 1× · see citing works
“In human cells, G4-forming sequences are highly correlated with R-loop-forming regions (Puget et al., 2019; Zheng et al., 2017; Zhang et al., 2020); therefore, our results suggest that some of the DSBs induced upon G4 stabilization by G4 ligands are associated with R-loop formation.”
BackgroundSon, J., Hannan, K. M., Poortinga, G., Hein, N., Cameron, D. P., Ganley, A. R. D., Sheppard, K. E., Pearson, R. B., Hannan, R. D., & Sanij, E. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00568 · Cited by 24 · see citing works
Blower, T. R., Bandak, A. F., Lee, A. S. Y., Austin, C. A., Nitiss, J. L., & Berger, J. M. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz579 · Cited by 19 · cited 2× · see citing works
“This indicates that, as observed for TOP2 poisons in a yeast complementation system (Blower et al., 2019), resistance to CX-5461 can be obtained through different protein modifications and is not strictly dependent on the catalytic function.”
BackgroundIn vitro Footprinting of Promoter Regions Within Supercoiled Plasmid DNA
Sun, D. (2009) · Methods in molecular biology · doi:10.1007/978-1-60327-418-0_14 · Cited by 12 · cited 1× · see citing works
“The increased BG4 signal observed in ETP-treated cells probably results from a global increase of DNA supercoiling by ETP, which would promote G4 formation as shown in several other studies (Sekibo and Fox, 2017; Sun, 2010; Sun and Hurley, 2009).”
ResultBombarde, O., Larminat, F., Gómez, D., Frit, P., Racca, C., Gomes, B., Guilbaud, N., & Calsou, P. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0767 · Cited by 9 · cited 2× · see citing works
“Targeted sequencing of TOP2A cDNA in five F14R clones revealed five different TOP2A mutations, confirming that TOP2A is the main mediator of F14512 cytotoxicity (Bombarde et al., 2017).”
BackgroundMethodSelf-citationSite-Specific Cleavage by Topoisomerase 2: A Mark of the Core Centromere
Mills, W. E., Spence, J. M., Fukagawa, T., & Farr, C. J. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19020534 · Cited by 9 · cited 1× · see citing works
“Moreover, several studies demonstrated that DNA topoisomerase 1 (TOP1) and TOP2 recog- nize and preferentially cleave DNA at regions forming stable secondary structures (Froelich- Ammon et al., 1994; Jonstrup et al., 2008; Mills et al., 2018; West and Austin, 1999).”
Backgroundde Campos‐Nebel, M., Palmitelli, M., & González‐Cid, M. (2016) · Cytometry Part A · doi:10.1002/cyto.a.22919 · Cited by 6 · see citing works
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Untangling the roles of TOP2A and TOP2B in transcription and cancer
Uusküla-Reimand, L., & Wilson, M. D. (2022) · Science Advances · doi:10.1126/sciadv.add4920 · Cited by 236 · see citing works
“The cytotoxicity of PDS primarily depends on the transcription of RNA polymerase II (Pol II); however, CX5461 treatment affects both RNA Pol I transcription of ribosomal DNA (rDNA) genes in the nucleolus and RNA Pol II transcription in the nucleus (62).”
BackgroundInfluentialHilton, 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 · see citing works
“Additional correlative studies were approved by the UHN research ethics board (14-8358).”
MethodG-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
Pan, M., Wright, W. C., Chapple, R., Zubair, A., Sandhu, M., Batchelder, J. E., Huddle, B. C., Low, J., Blankenship, K., Wang, Y., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26640-x · Cited by 79 · see citing works
Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies
Molinaro, C., Martoriati, A., & Cailliau, K. (2021) · Cancers · doi:10.3390/cancers13153819 · Cited by 93 · see citing works
Xu, H., & Hurley, L. H. (2022) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2022.129016 · Cited by 84 · see citing works
Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way Forward
Zisi, A., Bártek, J., & Lindström, M. S. (2022) · Cancers · doi:10.3390/cancers14092126 · Cited by 80 · see citing works
“TOP2A was identified as a target for CX-5461 in an independent study [154].”
BackgroundG-quadruplex resolution: From molecular mechanisms to physiological relevance
Sato, K., & Knipscheer, P. (2023) · DNA repair · doi:10.1016/j.dnarep.2023.103552 · Cited by 64 · see citing works
DNA folds threaten genetic stability and can be leveraged for chemotherapy
Zell, J., Sperti, F. R., Britton, S., & Monchaud, D. (2020) · RSC Chemical Biology · doi:10.1039/d0cb00151a · Cited by 58 · see citing works
Self-citationThe chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cells
Koh, G., Boushaki, S., Zhao, S., Pregnall, A., Sadiyah, F., Badja, C., Memari, Y., Georgakopoulos-Soares, I., & Nik-Zainal, S. (2023) · Nature Genetics · doi:10.1038/s41588-023-01602-9 · Cited by 45 · see citing works
“Proposed mechanisms underpinning therapeutic efficacy of CX-5461 include stabilizing G-quadruplexes (G4) and impeding topoisomerase II (TOP2) activity 9–11 .”
BackgroundTopoisomerase II poisons inhibit vertebrate DNA replication through distinct mechanisms
Ravenstein, S. X. V., Mehta, K. P. M., Kavlashvili, T., Byl, J. A. W., Zhao, R., Osheroff, N., Cortez, D., & Dewar, J. M. (2022) · The EMBO Journal · doi:10.15252/embj.2022110632 · Cited by 45 · see citing works
“Accordingly, G-quadruplex stabilizing agents CX-5461 and pyridostatin both act as TOP2 poisons at sites of transcription by stabilizing G-quadruplex structures (Olivieri et al , 2020; Bossaert et al , 2021).”
The G-quadruplex ligand CX-5461: an innovative candidate for disease treatment
Li, H.-X., He, Y.-M., Fei, J., Guo, M., Zeng, C., Yan, P.-J., Xu, Y., Qin, G., & Teng, F.-Y. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06473-8 · Cited by 37 · see citing works
“3) [89].”
G-quadruplexes are promoter elements controlling nucleosome exclusion and RNA polymerase II pausing
Esnault, C., Aabidine, A. Z. E., Robert, M.-C., Cucchiarini, A., Magat, T., Pigeot, A., Bouchouika, S., García-Oliver, E., Gawron, K., Basyuk, E., et al. (2023) · bioRxiv · doi:10.1038/s41588-025-02263-6 · Cited by 32 · see citing works
Zell, J., Duskova, K., Chouh, L., Bossaert, M., Chéron, N., Granzhan, A., Britton, S., & Monchaud, D. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab796 · Cited by 32 · see citing works
Self-citationTelomere Targeting Chimera Enables Targeted Destruction of Telomeric Repeat-Binding Factor Proteins
Wang, Z., Liu, J., Chen, H., Qiu, X., Xie, L., Kanıskan, H. Ü., Chen, X., Jin, J. J., & Wei, W. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c02783 · Cited by 32 · see citing works
Topoisomerase 1 activity during mitotic transcription favors the transition from mitosis to G1
Wiegard, A., Kuzin, V., Cameron, D. P., Grosser, J., Ceribelli, M., Mehmood, R., Ballarino, R., Valant, F., Grochowski, R., Karabogdan, I., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.10.015 · Cited by 31 · see citing works
G-quadruplexes and associated proteins in aging and Alzheimer’s disease
Kumar, M. J. V., Morales, R., & Tsvetkov, A. S. (2023) · Frontiers in Aging · doi:10.3389/fragi.2023.1164057 · Cited by 33 · see citing works
“G4DNA structures allow and inhibit transcription by recruiting proteins, blocking polymerases and topoisomerase poisoning, and keeping the nascent strand in a single-stranded conformation by the formation of a G4 structure on the nontranscribed strand (Balasubramanian et al., 2011; Berroyer and Kim, 2020; Bossaert et…”
BackgroundInduction of the alternative lengthening of telomeres pathway by trapping of proteins on DNA
Rose, A. M., Goncalves, T., Cunniffe, S. M. T., Geiller, H. E. B., Kent, T., Shepherd, S., Ratnaweera, M., O’Sullivan, R. J., Gibbons, R. J., & Clynes, D. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad150 · Cited by 28 · see citing works
Design, synthesis and anticancer activity of 2-arylimidazo[1,2-a]pyridinyl-3-amines
Yadav, U. P., Ansari, A. J., Arora, S., Joshi, G., Singh, T., Kaur, H., Dogra, N., Kumar, R., Kumar, S., Sawant, D. M., et al. (2021) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2021.105464 · Cited by 27 · see citing works
Regulation of RNA Polymerase I Stability and Function
Pitts, S., & Laiho, M. (2022) · Cancers · doi:10.3390/cancers14235776 · Cited by 22 · see citing works
CX-5461 Preferentially Induces Top2α-Dependent DNA Breaks at Ribosomal DNA Loci
Cameron, D. P., Sornkom, J., Alsahafi, S., Drygin, D., Poortinga, G., McArthur, G. A., Hein, N., Hannan, R. D., & Panov, K. I. (2024) · Biomedicines · doi:10.3390/biomedicines12071514 · Cited by 26 · see citing works
“Recently, a number of studies proposing alternative mechanisms of action (MOAs) for CX-5461 [18–23] were published, but some results of these studies were, in part, contradictory (for the latest review see [2] and this manuscript).”
BackgroundMethodInfluentialUV-induced G4 DNA structures recruit ZRF1 which prevents UV-induced senescence
Magis, A. D., Limmer, M., Mudiyam, V., Monchaud, D., Juranek, S., & Paeschke, K. (2023) · Nature Communications · doi:10.1038/s41467-023-42494-x · Cited by 23 · see citing works
“In higher eukaryotes, folded G4s can, under speci fi c conditions, serve as hotspots for DNA damage and negatively impact genome stability 26,27 by either acting as roadblocks to polymerase motion 2,42 or by trappingDNA-relatedenzymes(e.g.,TOP2A)ontheirsubstratesina structure-dependent manner 43,44 .”
BackgroundHarnessing the Nucleolar DNA Damage Response in Cancer Therapy
Xuan, J., Gitareja, K., Brajanovski, N., & Sanij, E. (2021) · Genes · doi:10.3390/genes12081156 · Cited by 24 · see citing works
“Indeed, a recent study has shown that CX-5461 may act as a DNA structure-driven TOP2poison at transcribed regions bearing G4 structures [123].”
BackgroundInfluentialA Synthetic Lethal Approach to Drug Targeting of G-Quadruplexes Based on CX-5461.
Jin, M., Hurley, L., & Xu, H. (2023) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2023.129384 · Cited by 23 · see citing works
PhpC modulates G-quadruplex-RNA landscapes in human cells
Mitteaux, J., Raevens, S., Wang, Z., Pirrotta, M., Valverde, I. E., Hudson, R. H. E., & Monchaud, D. (2023) · Chemical Communications · doi:10.1039/d3cc05155b · Cited by 24 · see citing works
From the TOP: Formation, recognition and resolution of topoisomerase DNA protein crosslinks
Wojtaszek, J. L., & Williams, R. S. (2024) · DNA repair · doi:10.1016/j.dnarep.2024.103751 · Cited by 23 · see citing works
Zhang, Y.-S., Cheng, Y., Luo, Q., Wu, T.-B., Huo, J.-F., Yin, M., Peng, H., Xiao, Y., Tong, Q.-Y., & You, H. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.3c09074 · Cited by 17 · see citing works
Therapeutic Use of G4-Ligands in Cancer: State-of-the-Art and Future Perspectives
Iachettini, S., Biroccio, A., & Zizza, P. (2024) · Pharmaceuticals · doi:10.3390/ph17060771 · Cited by 22 · see citing works
Sperti, F. R., Dupouy, B., Mitteaux, J., Pipier, A., Pirrotta, M., Chéron, N., Valverde, I. E., & Monchaud, D. (2022) · JACS Au · doi:10.1021/jacsau.2c00082 · Cited by 21 · see citing works
Self-citationG-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
“Recent genome-wide investigations under-score that these effects are not confined to promotors, but are rather observed across the genome ( 68–70 ).”
BackgroundSnyers, L., Laffer, S., Löhnert, R., Weipoltshammer, K., & Schöfer, C. (2022) · Scientific Reports · doi:10.1038/s41598-022-17923-4 · Cited by 21 · see citing works
Topoisomerase Regulation of Cancer Gene Expression
Baranello, L., Kouzine, F., & Levens, D. (2025) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-091724-010717 · Cited by 18 · see citing works
Ribosome Biogenesis and Function in Cancer: From Mechanisms to Therapy
Gitareja, K., Chelliah, S. S., Sanij, E., Sandhu, S. K., Kang, J., & Khot, A. S. (2025) · Cancers · doi:10.3390/cancers17152534 · Cited by 18 · see citing works
“The mechanism by which CX-5461 traps TOP2 on the DNA differs to classical TOP2 poisons due to its selectivity towards genomic regions characterised by high transcriptional activity and enrichment of G4 structures [176,179].”
Emerging roles of DNA topoisomerases in the regulation of R-loops
Patel, P. S., Krishnan, R., & Hakem, R. (2022) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2022.503450 · Cited by 17 · see citing works
Herbert, A. G. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105140 · Cited by 17 · see citing works
J, V. K. M., Mitteaux, J., Wang, Z., Wheeler, E., Tandon, N., Jung, S. Y., Hudson, R. H. E., Monchaud, D., & Tsvetkov, A. S. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.108040 · Cited by 17 · 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
“initially reported to inhibit POLR, but its real molecular target may be topoisomerase 2 at transcribed regions containing G4 [94,95].”
BackgroundPirh2-dependent DNA damage in neurons induced by the G-quadruplex ligand pyridostatin
Escarcega, R. D., Patil, A. A., Moruno-Manchon, J. F., Urayama, A., Marrelli, S. P., Kim, N., Monchaud, D., McCullough, L. D., & Tsvetkov, A. S. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105157 · Cited by 16 · see citing works
“Overly stabilized G4-DNA structures act as physical barriers for polymerases, leading to DNA damage via transcription-coupled repair poisoning (31) and/or Top2 trapping at G4 sites (17, 18, 32).”
BackgroundTargeting the ribosome to treat multiple myeloma
Maclachlan, K. H., Gitareja, K., Kang, J., Cuddihy, A., Cao, Y., Hein, N., Cullinane, C., Ang, C.-S., Brajanovski, N., Pearson, R., et al. (2024) · Molecular therapy. Oncology · doi:10.1016/j.omton.2024.200771 · Cited by 14 · see citing works
“34 TOP2a alleviates topological stress during transcription or replication by forming a transient TOP2a-DNA covalent complex (TOP2cc) and producing temporary DSBs. TOP2 inhibitors stabilize transient TOP2cc, leading to accumulation of cytotoxic DSBs, which may contribute to CX-5461-mediated DDR.”
BackgroundRoles of G4-DNA and G4-RNA in Class Switch Recombination and Additional Regulations in B-Lymphocytes
Dézé, O., Laffleur, B., & Cogné, M. (2023) · Molecules · doi:10.3390/molecules28031159 · Cited by 11 · see citing works
“Notably, the TOP1 topoisomerase also participates to CSR regulation by limiting cotranscriptional G4s formation, and its inhibition by the specific inhibitor camptothecin can inhibit CSR, while its genetic knock-down by contrast enhances CSR [173].”
BackgroundAdvances in research on malignant tumors and targeted agents for TOP2A (Review)
Zhou, T., Niu, Y., & Li, Y. (2024) · Molecular Medicine Reports · doi:10.3892/mmr.2024.13415 · Cited by 14 · see citing works
“Similarly, the G4 ligand pyridostatin (PdS) has been identified as a potent ToP2 poison (144).”
MATSUZAKI, K., Kumatoriya, K., Tando, M., Kometani, T., & Shinohara, M. (2022) · Scientific Reports · doi:10.1038/s41598-022-14374-9 · Cited by 13 · see citing works
Pitts, S. C., Liu, H., Ibrahim, A. F. M., Garg, A. K., Felgueira, C. M., Begum, A., Fan, W., Teh, S. S. K., Low, J., Ford, B. L., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102690 · Cited by 12 · see citing works
“Other chemotherapeutic drugs, such as actinomycin D, oxaliplatin and topoisomerase II poisons (CX-5461, anthracyclines, etoposide) also inhibit rRNA synthesis (54-60).”
BackgroundRaimer, H. M., Hou, P., Bartosik, A. R., Atkin, N. D., Wang, L., Wang, Z., Ratan, A., Zang, C., & Wang, Y. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae164 · Cited by 10 · see citing works
“Recent studies have demonstrated that G4s have a direct role in the recruitment of CTCF to DNA ( 77 ) and that the G4 stabilizing ligands (pyridostatin and CX5461) generate DSBs through a TOP2 poisoning mechanism, like etoposide ( 100 ,101 ).”
Yan, J., Bu, L., Wang, Y., Yao, H., Li, G., Zheng, K., & Huang, J. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf543 · Cited by 10 · see citing works
“Recent advancements have shed light on the mechanisms involved: ligand-stabilized G4s directly induce DNA damage by trapping topoisomerase II at G4 sites [ 19 , 20 ], and the spatial colocalization of G4s with DNA damage foci further supports their role as barriers to replication [ 21 , 22 ].”
Lehman, S. L., Schwartz, K., Maheshwari, S., Camphausen, K. A., & Tofilon, P. J. (2022) · Scientific Reports · doi:10.1038/s41598-022-07928-4 · Cited by 10 · see citing works
Ribosome-directed cancer therapies: the tip of the iceberg?
Howard, G. C., & Tansey, W. P. (2025) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2025.02.001 · Cited by 9 · see citing works
Ribosomal RNA transcription regulates splicing through ribosomal protein RPL22
Fan, W., Liu, H., Stachelek, G. C., Begum, A., Davis, C. E., Dorado, T. E., Ernst, G., Reinhold, W. C., Ozbek, B., Zheng, Q., et al. (2025) · Cell Chemical Biology · doi:10.1016/j.chembiol.2025.05.012 · Cited by 8 · see citing works
SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species
Demange, P., Joly, E., Marcoux, J., Zanon, P. R. A., Listunov, D., Rullière, P., Barthes, C., Noirot, C., Izquierdo, J.-B., Rozié, A., et al. (2022) · eLife · doi:10.7554/elife.73913 · Cited by 9 · see citing works
Self-citationGenome Instability Induced by Topoisomerase Misfunction
Nitiss, K. C., Bandak, A. F., Berger, J. M., & Nitiss, J. L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms251910247 · Cited by 8 · see citing works
“Recent studies also suggest that different DNA structures such as G4 quadruplex DNA may also affect topoisomerase-mediated DNA cleavage [23].”
BackgroundHow DNA secondary structures drive replication fork instability
Sethi, A., Fernández-Casañas, M., Delpino, B., & Coster, G. (2025) · DNA repair · doi:10.1016/j.dnarep.2025.103913 · Cited by 7 · see citing works
Jian, J., & Osheroff, N. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241311199 · Cited by 8 · see citing works
Peng, H., Zhang, Y.-S., Luo, Q., Wang, X., & You, H.-J. (2024) · Biophysics Reports · doi:10.52601/bpr.2024.240018 · Cited by 8 · see citing works
“Recent studies have revealed that the mechanism underpinning the therapeutic efficacy of CX-5461 includes stabilizing G-quadruplex formation and inhibiting topoisomerase II, causing DNA damage (Bossaert et al. 2021; Bruno et al. 2020; Koh et al. 2024; Pan et al. 2021).”
BackgroundHan, Z., & Wen, L. (2023) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v15.i7.1149 · Cited by 8 · see citing works
Simoes‐Sousa, S., Amin, N., Lane, K. A., Harrod, A., Pedersen, M., Pardo, M., Rasetti‐Escargueil, C., Kozik, Z., Begg, K., Ribeiro, A., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116277 · Cited by 7 · see citing works
Translating G-quadruplex ligands from bench to bedside: a Stephen Neidle’s legacy
Monchaud, D. (2024) · Medicinal Chemistry Research · doi:10.1007/s00044-024-03310-3 · Cited by 7 · see citing works
“…Pidnarulex stabilizes G4s and from there, triggers a series of G4-mediated cellular events including DNA damage (that has been exploited in chemically induced synthetic lethality cocktails) [75] and Top2 inhibition (the enzyme being physically trapped at ligand-stabilized G4 sites) [38, 76, 77].”
Fluorescence Detection of DNA/RNA G‐Quadruplexes (G4s) by Twice‐as‐Smart Ligands
Ledvinka, J., Sperti, F. R., Paragi, G., Pirrotta, M., Chéron, N., Valverde, I. E., Ménová, P., & Monchaud, D. (2024) · ChemMedChem · doi:10.1002/cmdc.202400829 · Cited by 7 · see citing works
Pharmacomodulation of G-quadruplexes in long non-coding RNAs dysregulated in colorectal cancer
Sharma, S., Mitteaux, J., Pipier, A., Pirrotta, M., Penouilh, M., Monchaud, D., & Datta, B. (2025) · BMC Biology · doi:10.1186/s12915-025-02322-8 · Cited by 6 · see citing works
Self-citationPang, Y., Cheng, M., Wang, J., Wang, R., Chen, X., Zhang, C., Yang, Y., Ji, T., Liu, M., Zhang, J., et al. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf939 · Cited by 7 · see citing works
“Initially, CX-5461 was thought to exert its anticancer effects primarily through RNA polymerase I inhibition and nucleolar stress [ 50 ]; recent studies suggest it also acts as a TOP2B poison [ 30–32 ].”
Roles, biological functions, and clinical significances of RHPN1-AS1 in cancer
Yu, F., He, H., & Zhou, Y. (2023) · Pathology - Research and Practice · doi:10.1016/j.prp.2023.154589 · Cited by 6 · see citing works
Ferreira, R., Hannan, K. M., Panov, K. I., Udumanne, T. P., George, A. J., Closa, A., Yuen, Z. W.-S., Eyras, E., Poh, P., Maclachlan, K. H., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.19.649466 · Cited by 7 · see citing works
Mazzoleni, V., Boichard, A., & Lamour, V. (2025) · Journal of Molecular Biology · doi:10.1016/j.jmb.2025.169384 · Cited by 5 · see citing works
Waisertreiger, I. S.-R., Ayele, K., Elshaikh, M. H., & Barlow, J. H. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2506939122 · Cited by 5 · see citing works
“The MaSat plasmid (a 471 bp fragment of MaSat (107) cloned into pBluescript II KS) was a gift by Professor Olga I. Podgornaya (Saint - Petersburg, Russia).”
Camarillo, R., Jimeno, S., & Huertas, P. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.742434 · Cited by 4 · see citing works
Reply to: The chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cellsPreprint
Kanwal, S., Brajanovski, N., Zhan, J., Chan, J., Rebello, R. J., Hofmann, O., Grimmond, S. M., Furic, L., Hannan, R. D., McArthur, G. A., et al. (2025) · medRxiv · doi:10.1101/2025.09.30.25336525 · Cited by 4 · see citing works
Luige, J., Conrad, T., Armaos, A., Louloupi, A., Vincent, A. I., Meierhofer, D., Gajhede, M., Tartaglia, G. G., & Ørom, U. A. (2025) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2025.06.027 · Cited by 3 · see citing works
Raevens, S., Danino, Y. M., Desingle, C., Sperti, F. R., Pirrotta, M., Mazzucotelli, L., Letissier, L., Hornstein, E., Cianférani, S., Hernandez‐Alba, O., et al. (2025) · ACS Bio & Med Chem Au · doi:10.1021/acsbiomedchemau.5c00162 · Cited by 3 · see citing works
Hile, S. E., Weissensteiner, M. H., Pytko, K. G., Dahl, J. M., Kejnovský, E., Kejnovská, I., Hedglin, M., Georgakopoulos‐Soares, I., Makova, K. D., & Eckert, K. A. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf352 · Cited by 3 · see citing works
“PDS treatment increases strand breaks in all phases of the mitotic cell cycle [ 73 ], and PDS cytotoxicity from strand breaks has been linked to topoisomerase II poisoning, especially in transcriptionally active regions [ 110 , 111 ].”
Malina, J., Kostrhunová, H., & Brabec, V. (2024) · Small · doi:10.1002/smll.202406814 · Cited by 2 · see citing works
Paul, S., Gutierrez, J. A., Bogar, A. R., Matthews, E. R., & Ward, M. C. (2026) · G3 Genes Genomes Genetics · doi:10.1093/g3journal/jkag008 · Cited by 2 · see citing works
“TOP2A has also been suggested to mediate effects of G-quadruplex ligands including CX (Bossaert et al. 2021), and the DNA-damaging effects of CX in ribosomal regions (Cameron et al. 2024).”
Malina, J., Kostrhunová, H., Aldrich-Wright, J. R., & Brabec, V. (2025) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2025.111534 · Cited by 2 · see citing works
Ribosomal RNA transcription governs splicing through ribosomal protein RPL22Preprint
Fan, W.-J., Liu, H., Stachelek, G. C., Begum, A., Davis, C. E., Dorado, T. E., Ernst, G., Reinhold, W. C., Ozbek, B., Zheng, Q., et al. (2024) · bioRxiv · doi:10.1101/2024.08.15.608201 · Cited by 2 · see citing works
“CX-5461, previously nominated as specific Pol I inhibitor (Bruno et al. 2017), has unequivocally been identified as a TOP2 targeting agent and conveys its therapeutic activity by this mechanism (Bruno et al. 2020; Bossaert et al. 2021; Pan et al. 2021; Xu and Hurley 2022).”
BackgroundDexheimer, T. S., Coussens, N. P., Silvers, T. E., Juneja, P., Jones, E., Gore, S. D., Kunkel, M. W., Doroshow, J. H., & Teicher, B. A. (2025) · SLAS DISCOVERY · doi:10.1016/j.slasd.2025.100284 · Cited by 1 · see citing works
DNA topological regulation in RNA polymerase II transcription
Bunch, H. (2026) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-026-00885-0
“A previous study reported that TOP2A is responsible for DNA break at G4 structures in transcription [84].”
Psalmon, G., Pipier, A., Barbotte, M., Hudson, R. H. E., Neidle, S., & Monchaud, D. (2026) · Genome biology · doi:10.1186/s13059-026-04035-9 · Cited by 1 · see citing works
“…PDS, whose DNA-damaging properties ( i.e. , its ability to trigger DSBs) are well-documented in a series of cell lines including U2OS, MDA-MB-231 (breast cancer) and HeLa cells [29, 32, 33, 43], and this was recently demonstrated for QN-302 in U2OS cells [61], with a particular focus on telomeres.”
Self-citationThe SMARCA4 subunit of the SWI/SNF complex prevents genome instability at G quadruplexes
Harrod, A., Feng, H., Ghaddar, N., Schiavoni, F., Lane, K. A., Wu, L., Zuazua‐Villar, P., Kozik, Z., Dobbs, F. M., van Eijk, P., et al. (2026) · Genome biology · doi:10.1186/s13059-026-04080-4 · Cited by 2 · see citing works
“The cytotoxicity of PDS has been shown to be mediated by its ability to induce DNA damage [42, 43].”
Teng, F.-Y., Zhang, B., Liu, Y.-X., Wu, Q., Xu, Y., Qin, G., & Li, H.-X. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.117229 · Cited by 1 · see citing works
Vandeuren, A. L., O’Dare, K., Wilson, R. H. C., van Eijk, P., Julio, L. R., MacLeod, S. G., Chee, E., Salpukas, A., Kriz, E. M., Lantz, G. A., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.10.627505 · Cited by 1 · see citing works
Local nucleolar surveillance mechanisms maintain rDNA stabilityPreprint
Liu, R., Xuan, J., Pan, J., Chelliah, S. S., Dmello, R., Cowley, K. J., Mendez, S., Zhang, Y., Gitareja, K., Wakefield, M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.20.633984 · Cited by 1 · see citing works
A Chemical-Genetic Interaction Matrix Reveals Drug Mechanism and Genetic ArchitecturePreprint
Coulombe‐Huntington, J., Bertomeu, T., Huard, C., Chatr‐aryamontri, A., St‐Cyr, D. J., Sánchez‐Osuna, M., Papadopoli, D. J., Normandin, K., Paydar, M., McLaughlan, S., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.28.701823 · Cited by 1 · see citing works
Yu, Z., Wu, J., Zhang, L., & Liu, S. (2022) · World Chinese Journal of Digestology · doi:10.11569/wcjd.v30.i3.128
Targeting DNA Junctions with Small Molecules for Therapeutic Applications in Oncology
Zell, J., & Monchaud, D. (2022) · Springer eBooks · doi:10.1007/978-981-16-1313-5_37-1
Targeting DNA Junctions with Small Molecules for Therapeutic Applications in Oncology
Zell, J., & Monchaud, D. (2023) · Springer eBooks · doi:10.1007/978-981-19-9776-1_37
Alhourani, F., Tauziet, M., Patouillard, J., Miotto, B., Baldin, V., Gennetier, A., George, S., Mialhe, X., Ribeyre, C., Pourquier, P., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.11.642623
Sun, Y., Hu, X., Huang, X., Zhou, W., Lan, S., Zhang, H., Wu, G., & Lei, L. (2025) · Cell Proliferation · doi:10.1111/cpr.70052
NPM1 mislocalization mediated by RNA Pol I inhibition alters chromatin landscapePreprint
Esteve, P. O., Sen, S., Raman, K., Unnikrishnan, A., & Pradhan, S. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.28.684736
Psalmon, G., Pipier, A., Barbotte, M., Hudson, R. H. E., Neidle, S., & Monchaud, D. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.06.704351
“To this end, we first characterize here the ability of QN-302 and PDS (used as a control) (32, 33) to engage G4s in a model of human cancer (HeLa cells) by in situ click imaging.”
Self-citationThe UV potentiated mutational signature of clinical stage G-quadruplex binder CX5461Preprint
Zaikova, E., Yap, D., Sarvar, A., Hafezi, A., Tan, J., Cerda, V., Li, K., Lai, D., Gelmon, K. A., Hilton, J. F., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.10.717570
“…induce double-stranded breaks in epithelial cells by at least two mechanisms (polymerase stalling 11 , helicase and topoisomerase interference 10,12 ), have strong selective activity with loss of specific DNA repair functions including HRD, non-homologous end joining (NHEJ), polymerase-theta…”
The UVA-induced single-base mutational signature of CX-5461 in human cells
Zaikova, E., Yap, D., Sarvar, A., Hafezi, A., Tan, J., Cerda, V., Li, K., Lai, D., Gelmon, K. A., Hilton, J. F., et al. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag836
“G4 stabilizers and CX-5461 have been linked to replication/transcription-associated DNA damage [ 24 ] and topoisomerase-2-associated DNA breaks, which have been associated with G4 ligands [ 25 , 26 ].”
RAD54L coordinates the nucleolar DNA damage response to maintain rDNA stability
Liu, R., Xuan, J., Cerra, C., Stojnic, N., Pan, J., Chelliah, S. S., Mendez, S., Dmello, R., Cowley, K. J., Zhang, Y., et al. (2026) · The EMBO Journal · doi:10.1038/s44318-026-00864-3
“CX-5461 induces replication stress associated with G4 stabilization and/or TOP II trapping at rDNA loci (Bossaert et al, 2021; Cameron et al, 2024; Xu et al, 2017).”
Bartosik, A. R., Bujnowska, M., Stovall, D. B., Ratan, A., & Wang, Y. (2026) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2026.2710103
A complex mutational signature generated by cytarabine resistance
Cao, D., Yin, M., Bertoli, R. M., Zhang, Z., Lu, A., Zhu, J., Baslan, T., Chung, Y. J., Negi, V., Meltzer, P. S., et al. (2026) · NAR Cancer · doi:10.1093/narcan/zcag017
Stress-induced helicase DHX36 controls neuroinflammation.
J., V., Escarcega, R. D., Tan, C.-F., Moruno-Manchon, J., Urayama, A., Marrelli, S., Morales, R., McCullough, L. D., Kim, N., Jung, S.-Y., et al. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.113584
Non-B DNA at the Interface of Metabolism, Genome Stability, and Inflammation
Megalovasilis, G., Bochalis, E., Chartoumpekis, D., Vasquez, K. M., & Georgakopoulos-Soares, I. (2026) · Genes · doi:10.3390/genes17101301
“Mechanistically, the cytotoxicity of G4 ligands has been linked to transcription-associated topoisomerase 2 α activity and consequent DNA damage [158], highlighting that the same structures that act as endogenous mutation hotspots can also be utilized therapeutically.”
- Authors
- Bossaert, M., Pipier, A., Riou, J.-F., Noirot, C., Nguyên, L.-T., Serre, R.-F., Bouchez, O., Defrancq, E., Calsou, P., Britton, S., & Gomez, D.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Structure et Instabilité des Génomes, Muséum National d’Histoire Naturelle, CNRS, INSERM, Paris, France
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- INRAE, US 1426, GeT-PlaGe, Genotoul, Castanet-Tolosan, France
- Département de Chimie Moléculaire, UMR CNRS 5250, Université Grenoble Alpes, Grenoble, France
- Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
- Corresponding author
- Calsou, Patrick
- Britton, Sébastien
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2021-06-28
- Volume
- 10
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC8279764
- OpenAlex
- W3177139153
- Cited by
- 97
- References
- 117
- Citations by year
- 2026: 14 · 2025: 24 · 2024: 17 · 2023: 18 · 2022: 16 · 2021: 7 · 2020: 1
- FWCI
- 4.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- HAL (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Agence Nationale de la Recherche (ANR-17-CE18-0002-01, ANR-16-CE11-0006-01, ANR-10-INBS-09)
- Cancéropôle Grand Ouest (Emergence funding "CX-Break")
- Ligue Contre le Cancer (Equipe Labellisée 2018)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
- Keywords
- G-quadruplex ligands, TOP2A, DNA double-strand breaks, clastogenicity, pyridostatin, CX-5461, topoisomerase I, transcription elongation, cytotoxicity
- MeSH terms
- Poly-ADP-Ribose Binding Proteins, RNA-Seq, Aminoquinolines, Antineoplastic Agents, Cell Line, Cell Survival, Colony-Forming Units Assay, DNA Topoisomerases, Type II, DNA Topoisomerases, Type I, Humans, Naphthyridines, Picolinic Acids, Gene Expression Regulation, Enzymologic, Polymorphism, Single Nucleotide, RNA Interference, Cell Proliferation, Benzothiazoles, DNA Breaks, Double-Stranded, G-Quadruplexes
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