Targeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting Compounds
Open accessAbstract
G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers. Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks. We have previously shown that HR facilitates telomere replication. Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR. Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability. Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency. PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7. Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition.
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This effect seems to be aggravated in cells with an impaired DNA repair machinery and deficiencies in homologous recombination.
“This effect seems to be aggravated in cells with an impaired DNA repair machinery and deficiencies in homologous recombination. (72).”
From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [72]
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BackgroundInfluentialSelf-citationMammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient Replication
Sfeir, A., Kosiyatrakul, S. T., Hockemeyer, D., MacRae, S. L., Karlseder, J., Schildkraut, C. L., & de Lange, T. (2009) · Cell · doi:10.1016/j.cell.2009.06.021 · Cited by 990 · cited 2× · see citing works
“G4 Structure Stabilization Exacerbates the Telomere Fragility in Brca2-Deleted MEFs Telomere fragility indicates a telomere replication defect (Martı́nez et al., 2009; Sfeir et al., 2009), which is thought to stem from the potential of telomere DNA sequences to adopt G4 secondary structures known to obstruct replicati…”
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“DNA Fiber Assay DNA fiber assays were performed as described previously (Jackson and Pombo, 1998).”
MethodG-quadruplex structures: in vivo evidence and function
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“In vitro, G-rich ssDNA can adopt secondary structures known as G4s under physiological-like conditions (Lipps and Rhodes, 2009).”
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“In western blot analyses (Figure 3F), PDS and PhenDC both induced apoptosis specifically in RAD51-deficient cells, detected by cleaved PARP1 and gH2AX expression, a well-established marker for DNA damage that is also induced by apoptosis (Rogakou et al., 2000).”
BackgroundSmall-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 8× · see citing works
“G4 structures have been subsequently detected with several other structure-specific antibodies (Biffi et al., 2013; Henderson et al., 2014; Schaffitzel et al., 2001) and interacting small molecules (Lam et al., 2013; Müller et al., 2010; Rodriguez et al., 2012).”
InfluentialSelf-citationSchaffitzel, C., Berger, I., Postberg, J., Hanes, J., Lipps, H., & Plückthun, A. (2001) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.141229498 · Cited by 610 · cited 2× · see citing works
“G4 structures have been subsequently detected with several other structure-specific antibodies (Biffi et al., 2013; Henderson et al., 2014; Schaffitzel et al., 2001) and interacting small molecules (Lam et al., 2013; Müller et al., 2010; Rodriguez et al., 2012).”
BackgroundREV7 counteracts DNA double-strand break resection and affects PARP inhibition
Xu, G., Chapman, J. R., Brandsma, I., Yuan, J., Mistrík, M., Bouwman, P., Bártková, J., Gogola, E., Warmerdam, D. O., Barazas, M., et al. (2015) · Nature · doi:10.1038/nature14328 · Cited by 594 · cited 8× · see citing works
“Strikingly, olaparib-resistant Brca1-deficient cells lacking REV7 or 53BP1 expression (Brca1 / shREV7; Brca1 / 53BP1-deficient) were hypersensitive to PDS (Figures 7A, 7B, S7A, and S7B).”
BackgroundMethodInfluentialRad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis
Hashimoto, Y., Chaudhuri, A. R., Lopes, M., & Costanzo, V. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1927 · Cited by 537 · cited 2× · see citing works
“HR factors act to stabilize stalled replication forks by preventing their nucleolytic degradation (Hashimoto et al., 2010; Schlacher et al., 2011) to restart arrested forks (Lambert et al., 2010) and to repair double-strand breaks (DSBs) arising from disintegrated forks (Aze et al., 2013).”
BackgroundRodriguez, R., Müller, S., Yeoman, J. A., Trentesaux, C., Riou, J.-F., & Balasubramanian, S. (2008) · Journal of the American Chemical Society · doi:10.1021/ja805615w · Cited by 517 · cited 3× · see citing works
“Supporting this concept, treatment with G4-stabilizing compounds induces telomere dysfunction (Gomez et al., 2006; Rodriguez et al., 2008; Salvati et al., 2007; Tahara et al., 2006).”
BackgroundMethodLoss of 53BP1 Causes PARP Inhibitor Resistance in Brca1 -Mutated Mouse Mammary Tumors
Jaspers, J. E., Kersbergen, A. J., Boon, U., Sol, W., van Deemter, L., Zander, S. A. L., Drost, R., Wientjens, E., Ji, J. J., Aly, A., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0049 · Cited by 515 · cited 5× · see citing works
“Moreover, ionizing radiation (IR)-induced RAD51 foci assemble in olaparib-resistant Brca1 / , 53BP1deficient cells (albeit not at the same level as in Brca1+/+ cells), but not in olaparib-sensitive Brca1 / tumor-derived cells (Jaspers et al., 2013).”
BackgroundMethodInfluentialG-quadruplex structures are stable and detectable in human genomic DNA
Lam, E. Y. N., Beraldi, D., Tannahill, D., & Balasubramanian, S. (2013) · Nature Communications · doi:10.1038/ncomms2792 · Cited by 455 · cited 2× · see citing works
“450 Molecular Cell 61, 449–460, February 4, 2016 a2016 The Author damage at genomic sites with predicted G4-forming potential (Lam et al., 2013; Rodriguez et al., 2012).”
BackgroundDetection of G-quadruplex DNA in mammalian cells
Henderson, A., Wu, Y.-L., Huang, Y.-C., Chavez, E., Platt, J., Johnson, F., Brosh, R., Sen, D., & Lansdorp, P. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt957 · Cited by 443 · cited 1× · see citing works
“G4 structures have been subsequently detected with several other structure-specific antibodies (Biffi et al., 2013; Henderson et al., 2014; Schaffitzel et al., 2001) and interacting small molecules (Lam et al., 2013; Müller et al., 2010; Rodriguez et al., 2012).”
BackgroundMartínez, P., Thanasoula, M., Muñoz, P., Liao, C., Tejera, Á. M., McNees, C. J., Flores, J. M., Fernández-Capetillo, Ó., Tarsounas, M., & Blasco, M. A. (2009) · Genes & Development · doi:10.1101/gad.543509 · Cited by 367 · cited 2× · see citing works
“G4 Structure Stabilization Exacerbates the Telomere Fragility in Brca2-Deleted MEFs Telomere fragility indicates a telomere replication defect (Martı́nez et al., 2009; Sfeir et al., 2009), which is thought to stem from the potential of telomere DNA sequences to adopt G4 secondary structures known to obstruct replicati…”
BackgroundSelf-citationRibeyre, 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
“This suggested a role for HR in fork restart when Pif1 activity is abrogated (Ribeyre et al., 2009).”
BackgroundExistence and consequences of G-quadruplex structures in DNA
Murat, P., & Balasubramanian, S. (2014) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2013.10.012 · Cited by 346 · cited 1× · see citing works
“Several lines of evidence support a similar function in vivo for these factors, essential to preserve genome stability during DNA replication (Murat and Balasubramanian, 2014).”
BackgroundEpigenetic Instability due to Defective Replication of Structured DNA
Sarkies, P., Reams, C., Simpson, L. J., & Sale, J. E. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.11.009 · Cited by 302 · cited 2× · see citing works
“Plasmid-Based Replication Assay Plasmid-based replication assays were performed as previously described (Sarkies et al., 2010; Szüts et al., 2008) with modifications listed in Supplemental Experimental Procedures.”
MethodSelf-citationRAD51 paralogs: roles in DNA damage signalling, recombinational repair and tumorigenesis.
Suwaki, N., Klare, K., & Tarsounas, M. (2011) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2011.07.019 · Cited by 294 · cited 1× · see citing works
“BRCA2 promotes recombination reactions by loading the RAD51 recombinase onto single-stranded DNA (ssDNA) in concert with the family of proteins known as the RAD51 paralogs, of which RAD51C is a member (Suwaki et al., 2011).”
BackgroundSelf-citationder Zwet, M. K.-V., Overkamp, W. J., van Lange, R. E. E., Essers, J., van Duijn-Goedhart, A., Wiggers, I., Swaminathan, S., van Buul, P. V., Errami, A., Tan, R., et al. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.2.669-679.2002 · Cited by 267 · cited 1× · see citing works
“The same specific elimination by PDSwas observed for BRCA2-deficient V-C8 hamster cells (Kraakman-van der Zwet et al., 2002; Figure S2A) and Brca2 / mouse mammary tumor-derived cells (Figure S2B).”
BackgroundTelomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect
Salvati, E., Leonetti, C., Rizzo, A., Scarsella, M., Mottolese, M., Galati, R., Sperduti, I., Stevens, M. F. G., D’Incalci, M., Blasco, M., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32461 · Cited by 266 · cited 5× · see citing works
“Instead, we tested in our cellular models a previously reported G4-stabilizing drug, RHPS4 (Gavathiotis et al., 2003; Gowan et al., 2001; Heald et al., 2002), with well-characterized pharmacological features (Leonetti et al., 2008; Salvati et al., 2007).”
BackgroundMethodResultInfluentialSelf-citationStrand-Specific Postreplicative Processing of Mammalian Telomeres
Bailey, S. M., Cornforth, M. N., Kurimasa, A., Chen, D. J., & Goodwin, E. H. (2001) · Science · doi:10.1126/science.1062560 · Cited by 257 · cited 2× · see citing works
“Chromosome Orientation FISH and IF-FISH For CO-FISH, cells were plated at 50%–60% confluency and treated with 10 mM bromodeoxyuridine (BrdU) for 20 hr. Colcemid (0.2 mg/ml) was added to the cells 4–6 hr before metaphases were processed for CO-FISH as previously described (Bailey et al., 2001).”
MethodInfluentialTahara, H., Shin‐ya, K., Seimiya, H., Yamada, H., TSURUO, T., & Ide, T. (2005) · Oncogene · doi:10.1038/sj.onc.1209217 · Cited by 238 · cited 1× · see citing works
“Supporting this concept, treatment with G4-stabilizing compounds induces telomere dysfunction (Gomez et al., 2006; Rodriguez et al., 2008; Salvati et al., 2007; Tahara et al., 2006).”
BackgroundGowan, S. M., Heald, R. A., Stevens, M. F. G., & Kèlland, L. R. (2001) · Molecular Pharmacology · doi:10.1124/mol.60.5.981 · Cited by 229 · cited 12× · see citing works
“Instead, we tested in our cellular models a previously reported G4-stabilizing drug, RHPS4 (Gavathiotis et al., 2003; Gowan et al., 2001; Heald et al., 2002), with well-characterized pharmacological features (Leonetti et al., 2008; Salvati et al., 2007).”
MethodInfluentialTelomere Maintenance Requires the RAD51D Recombination/Repair Protein
Tarsounas, M., Muñoz, P., Claas, A., Smiraldo, P. G., Pittman, D. L., Blasco, M. A., & West, S. C. (2004) · Cell · doi:10.1016/s0092-8674(04)00337-x · Cited by 216 · cited 3× · see citing works
“For IF-FISH, metaphases were spun onto coverslips using a cytospin apparatus (Cytospin 4, Fisher) and subjected to immunofluorescence staining as described (Tarsounas et al., 2004).”
MethodInfluentialSelf-citationGómez, D., Wenner, T., Brassart, B., Douarre, C., O’Donohue, M.-F., El‐Khoury, V., Shin‐ya, K., Morjani, H., Trentesaux, C., & Riou, J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605828200 · Cited by 207 · cited 1× · see citing works
“Supporting this concept, treatment with G4-stabilizing compounds induces telomere dysfunction (Gomez et al., 2006; Rodriguez et al., 2008; Salvati et al., 2007; Tahara et al., 2006).”
BackgroundSmall-molecule-mediated G-quadruplex isolation from human cells
Müller, S., Kumari, S., Rodriguez, R., & Balasubramanian, S. (2010) · Nature Chemistry · doi:10.1038/nchem.842 · Cited by 204 · cited 2× · see citing works
“, 2001) and interacting small molecules (Lam et al., 2013; Müller et al., 2010; Rodriguez et al., 2012).”
BackgroundLambert, 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 · see citing works
Heyer, W., & Kohli, J. (2005) · Experientia · doi:10.1007/bf01924001 · Cited by 192 · cited 2×
“, 2011) to restart arrested forks (Lambert et al., 2010) and to repair double-strand breaks (DSBs) arising from disintegrated forks (Aze et al.”
BackgroundZimmermann, M., Kibe, T., Kabir, S., & de Lange, T. (2014) · Genes & Development · doi:10.1101/gad.251611.114 · Cited by 189 · cited 1× · see citing works
“The latter process is likely mediated by the shelterin component TRF1, which recruits BLM helicase to telomeres to unwind G4 structures (Zimmermann et al., 2014).”
BackgroundGavathiotis, E., Heald, R., Stevens, M. F., & Searle, M. (2003) · Journal of Molecular Biology · doi:10.1016/j.jmb.2003.09.018 · Cited by 171 · cited 2× · see citing works
“Instead, we tested in our cellular models a previously reported G4-stabilizing drug, RHPS4 (Gavathiotis et al., 2003; Gowan et al., 2001; Heald et al., 2002), with well-characterized pharmacological features (Leonetti et al., 2008; Salvati et al., 2007).”
MethodPiazza, A., Boulé, J., Lopes, J., Mingo, K., Largy, E., Teulade-Fichou, M., & Nicolas, A. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq136 · Cited by 166 · cited 2× · see citing works
“Moreover, RAD51 depletion sensitized HEK293T cells to theG4 ligand PhenDC (Figure 3E; Piazza et al., 2010).”
BRCA2 acts as a RAD51 loader to facilitate telomere replication and capping
Badie, S., Escandell, J. M., Bouwman, P., Carlos, A. R., Thanasoula, M., Gallardo, M. M., Suram, A., Jaco, I., Benitez, J. J., Herbig, U., et al. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1943 · Cited by 164 · cited 5× · see citing works
“HR factors, including BRCA2 and RAD51, are required to facilitate telomere replication and to prevent telomere shortening (Badie et al., 2010).”
BackgroundInfluentialSelf-citationGenomes and G-Quadruplexes: For Better or for Worse
Tarsounas, M., & Tijsterman, M. (2013) · Journal of Molecular Biology · doi:10.1016/j.jmb.2013.09.026 · Cited by 124 · cited 2× · see citing works
“Although G4s are thought to positively regulate key cellular processes, they can also obstruct replication-fork progression, leading to genomic instability (Tarsounas and Tijsterman, 2013).”
BackgroundSelf-citationHeald, R., Modi, C., Cookson, J., Hutchinson, I., Laughton, C., Gowan, S. M., Kèlland, L., & Stevens, M. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm011015q · Cited by 106 · see citing works
Leonetti, C., Scarsella, M., Riggio, G., Rizzo, A., Salvati, E., D'Incalci, M., Staszewsky, L., Frapolli, R., Stevens, M. F., Stoppacciaro, A., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0941 · Cited by 92 · cited 3× · see citing works
“In line with previous publications reporting the antitumor effect of RHPS4 (Leonetti et al., 2008; Salvati et al., 2007), this drug repressed growth of BRCA2-proficient tumors as assessed by tumor weight inhibition (TWI) (22%, Figure 6D).”
MethodResultSelf-citationA Syngeneic Variance Library for Functional Annotation of Human Variation: Application to BRCA2
Hucl, T., Rago, C., Gallmeier, E., Brody, J., Gorospe, M., & Kern, S. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-6189 · Cited by 84 · cited 2× · see citing works
“G4-stabilizing compounds are toxic to BRCA1- and BRCA2-deficient cells, highlighting their therapeutic potential in targeting BRCA deficiency.”
BackgroundMethodEvers, B., Schut, E., van der Burg, E., Braumuller, T. M., Egan, D. A., Holstege, H. H., Edser, P. A. H., Adams, D. J., Wade‐Martins, R., Bouwman, P., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-2434 · Cited by 78 · cited 1× · see citing works
“Quantification of fragmented telomeric COFISH signals further demonstrated the bias toward fragility of the G-rich telomeric strand in Cre-treated Brca2F/- and Mo Rad51cF/F MEFs (Figures 1D and 1E) as well as in a Brca2 / mouse mammary tumor-derived cell line (Evers et al., 2010; Figure S1D).”
BackgroundSzüts, D., Marcus, A. P., Himoto, M., Iwai, S., & Sale, J. E. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn651 · Cited by 67 · cited 4× · see citing works
“To further investigate this concept, we used a plasmid-based replication assay (Szüts et al., 2008) in H1299 cells harboring inducible small hairpin RNA (shRNA) against RAD51C or BRCA2.”
MethodInfluentialSelf-citationDNA replication and homologous recombination factors: acting together to maintain genome stability
Aze, A., Zhou, J., Costa, A., & Costanzo, V. (2013) · Chromosoma · doi:10.1007/s00412-013-0411-3 · Cited by 53 · cited 1× · see citing works
“HR factors act to stabilize stalled replication forks by preventing their nucleolytic degradation (Hashimoto et al., 2010; Schlacher et al., 2011) to restart arrested forks (Lambert et al., 2010) and to repair double-strand breaks (DSBs) arising from disintegrated forks (Aze et al., 2013).”
BackgroundCarlos, A. R., Escandell, J. M., Kotsantis, P., Suwaki, N., Bouwman, P., Badie, S., Folio, C., Benitez, J. J., Goméz-López, G., Pisano, D. G., et al. (2013) · Nature Communications · doi:10.1038/ncomms3697 · Cited by 45 · cited 1× · see citing works
“BRCA gene abrogation is associatedwith the same responses (Carlos et al., 2013).”
BackgroundSelf-citationErratum to: BRCA1 and CtIP promote alternative non‐homologous end‐joining at uncapped telomeres
Badie, S., Carlos, A. R., Folio, C., Okamoto, K., Bouwman, P., Jonkers, J., & Tarsounas, M. (2015) · The EMBO Journal · doi:10.15252/embj.201570610 · Cited by 42 · cited 2× · see citing works
“Preparation of Metaphase Spreads and Telomere FISH Metaphase spread preparation and telomeric FISH were performed as previously described (Badie et al., 2015).”
MethodSelf-citationHow homologous recombination maintains telomere integrity
Tacconi, E. M., & Tarsounas, M. (2014) · Chromosoma · doi:10.1007/s00412-014-0497-2 · Cited by 17 · cited 1× · see citing works
“HR Is Required for Effective Replication of Genomic Regions with G4-Forming Potential HR factors have previously been implicated in telomere maintenance (Tacconi and Tarsounas, 2015).”
BackgroundSelf-citation
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- Bouwman P. Jonkers J. Molecular pathways: how can BRCA-mutated tumors become resistant to PARP inhibitors? Clin. Cancer Res. 20 2014 540 547 24270682
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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 · see citing works
The Structure and Function of DNA G-Quadruplexes
Spiegel, J., Adhikari, S., & Balasubramanian, S. (2020) · Trends in Chemistry · doi:10.1016/j.trechm.2019.07.002 · Cited by 920 · see citing works
“G4 ligands such as pyridostatin and RHPS4 cause DNA double-strand breaks in cancer cells and activate DNA repair pathways [47,117].”
BackgroundInfluentialDNA G-quadruplexes in the human genome: detection, functions and therapeutic potential
Hänsel‐Hertsch, R., Antonio, M. D., & Balasubramanian, S. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.3 · Cited by 882 · see citing works
CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours
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A genetic map of the response to DNA damage in human cells
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“Like pyridostatin, CX5461 shows activity against HR-deficient cells and tumors (Xu et al., 2017; Zimmer et al., 2016), suggesting a common mechanism of action.”
BackgroundG-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 · see citing works
“BRCA1, BRCA2, Rad51 deficient cells) exhibited slow growth, fragile telomeres, DNA double strand breaks and checkpoint activation [94].”
BackgroundClinical and translational advances in ovarian cancer therapy
Konstantinopoulos, P. A., & Matulonis, U. A. (2023) · Nature Cancer · doi:10.1038/s43018-023-00617-9 · Cited by 399 · see citing works
Quadruplex nucleic acids as targets for anticancer therapeutics
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The antitumorigenic roles of BRCA1–BARD1 in DNA repair and replication
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“G4 ligands, including PDS, were recently shown to be more active in reducing the proliferation of BRCA1/2-deficient cancer cells by accumulating DNA damage, chromosomal aberrations, and persistent checkpoint activation (6, 7).”
BackgroundThe impact of replication stress on replication dynamics and DNA damage in vertebrate cells
Técher, H., Koundrioukoff, S., Nicolas, A. G., & Debatisse, M. (2017) · Nature Reviews Genetics · doi:10.1038/nrg.2017.46 · Cited by 271 · see citing works
Landscape of G-quadruplex DNA structural regions in breast cancer
Hänsel-Hertsch, R., Simeone, A., Shea, A., Hui, W. W. I., Zyner, K. G., Marsico, G., Rueda, O. M., Bruna, A., Martin, A., Zhang, X., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0672-8 · Cited by 223 · see citing works
Interplay between Fanconi anemia and homologous recombination pathways in genome integrity
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“FANCD 2 also inhibits FANCI-mediated dormant origin firing, independently of its monoubiquitination status.”
InfluentialSelf-citationMin, J., Wright, W. E., & Shay, J. W. (2017) · Molecular and Cellular Biology · doi:10.1128/mcb.00226-17 · Cited by 194 · see citing works
“Treatment with the G-quadruplex (here referred to as G4) ligand PDS (pyridostatin) induced more fragile telomeres, as previously reported (17, 18).”
BackgroundMethodBRCA2 abrogation triggers innate immune responses potentiated by treatment with PARP inhibitors
Reisländer, T., Lombardi, E. P., Groelly, F. J., Miar, A., Porru, M., Vito, S. D., Wright, B., Lockstone, H. E., Biroccio, A., Harris, A. L., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11048-5 · Cited by 192 · see citing works
Self-citationTranscription–replication conflicts underlie sensitivity to PARP inhibitors
Petropoulos, M., Karamichali, A., Rossetti, G. G., Freudenmann, A., Iacovino, L. G., Dionellis, V. S., Sotiriou, S. K., & Halazonetis, T. D. (2024) · Nature · doi:10.1038/s41586-024-07217-2 · Cited by 209 · see citing works
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G-Quadruplexes at Telomeres: Friend or Foe?
Bryan, T. M. (2020) · Molecules · doi:10.3390/molecules25163686 · Cited by 185 · see citing works
Mutant ATRX: uncovering a new therapeutic target for glioma
Haase, S., Garcia-Fabiani, M. B., Carney, S. V., Altshuler, D. B., Núñez, F. J., Mendez, F., Núñez, F. M., Lowenstein, P. R., & Castro, M. G. (2018) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2018.1487953 · Cited by 158 · see citing works
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Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities
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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
“The knowledge came from observations in cancer cells deficient for BRCA1/2 genes, critical players of HRR, as G4 binders were shown to be more active in DSB accumulation and persistent checkpoint activation in these cell types (112).”
BackgroundZhi-yin, S., Wang, X., Cheng, S.-Q., Su, X., & Ou, T. (2019) · Molecules · doi:10.3390/molecules24030396 · Cited by 135 · see citing works
“PDS increases telomere fragility in BRCA2-deficient cells via stabilization of the G-quadruplex in the telomeric region, and thus reduces proliferation of homologous recombination (HR)-defective cells by inducing double-strand breaks accumulation and checkpoint activation, and deregulating G2/M progression [168].”
BackgroundPOLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells.
Belan, O., Sebald, M., Adamowicz, M., Anand, R., Vančevska, A., Neves, J., Grinkevich, V., Hewitt, G., Segura-Bayona, S., Bellelli, R., et al. (2022) · Molecules and Cells · doi:10.1016/j.molcel.2022.11.008 · Cited by 115 · see citing works
Przetocka, S., Porro, A., Bolck, H. A., Walker, C., Lezaja, A., Trenner, A., von Aesch, C., Himmels, S.-F., D’Andrea, A. D., Ceccaldi, R., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.09.014 · Cited by 122 · see citing works
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Self-citationLigand-induced native G-quadruplex stabilization impairs transcription initiationPreprint
Li, C., Wang, H., Yin, Z., Fang, P., Xiao, R., Xiang, Y., Wang, W., Li, Q., Huang, B., Huang, J., et al. (2021) · Genome Research · doi:10.1101/gr.275431.121 · Cited by 115 · see citing works
“The application of G4 ligands as potential anticancer drugs is currently being evaluated (Zimmer et al. 2016; Zyner et al. 2019), with some of them currently reaching advanced phase I and phase II trials as candidate therapeutic agents (Drygin et al.”
BackgroundInfluentialExploiting replication gaps for cancer therapy
Cong, K., & Cantor, S. B. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.04.023 · Cited by 104 · see citing works
BRCA1 gene: function and deficiency
Takaoka, M., & Miki, Y. (2017) · International Journal of Clinical Oncology · doi:10.1007/s10147-017-1182-2 · Cited by 126 · see citing works
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“GAGTGTTTCCC_TTTTTT (65) into the EZ-Tet-pLKO-Hygro vector”
Genetic interactions of G-quadruplexes in humans
Zyner, K. G., Mulhearn, D. S., Adhikari, S., Cuesta, S. M., Antonio, M. D., Erard, N., Hannon, G. J., Tannahill, D., & Balasubramanian, S. (2019) · eLife · doi:10.7554/elife.46793 · Cited by 136 · see citing works
“It is reassuring that in this list we independently validated the known G4 sensitisers BRCA1/2, ATRX and HERC2 (McLuckie et al., 2013; Wang et al., 2019; Watson et al., 2013; Wu et al., 2018; Xu et al., 2017; Zimmer et al., 2016; Figure 3D).”
BackgroundResultInfluentialHow to untie G-quadruplex knots and why?
Lejault, P., Mitteaux, J., Sperti, F. R., & Monchaud, D. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.01.015 · Cited by 96 · see citing works
FANCD2 limits replication stress and genome instability in cells lacking BRCA2
Michl, J., Zimmer, J., Buffa, F. M., McDermott, U., & Tarsounas, M. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3252 · Cited by 95 · see citing works
Self-citationG-quadruplex stabilization via small-molecules as a potential anti-cancer strategy
Awadasseid, A., Ma, X., Wu, Y., & Zhang, W. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111550 · Cited by 95 · see citing works
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Exploiting synthetic lethality to target BRCA1/2-deficient tumors: where we stand
Patel, P. S., Algouneh, A., & Hakem, R. (2021) · Oncogene · doi:10.1038/s41388-021-01744-2 · Cited by 94 · see citing works
RTEL1 suppresses G-quadruplex-associated R-loops at difficult-to-replicate loci in the human genome
Wu, W., Bhowmick, R., Vogel, I., Özer, Ö., Ghisays, F., Thakur, R. S., León, E., Richter, P. H., Ren, L., Petrini, J. H. J., et al. (2020) · Nature Structural & Molecular Biology · doi:10.1038/s41594-020-0408-6 · Cited by 92 · see citing works
Mechanisms of DNA Replication and Repair: Insights from the Study of G-Quadruplexes
Bryan, T. M. (2019) · Molecules · doi:10.3390/molecules24193439 · Cited by 91 · see citing works
“cells lacking HR proteins BRCA1 and BRCA2 to death caused by G4-stabilizing ligands [17,70].”
BackgroundInfluentialPotential Roles for G-Quadruplexes in Mitochondria
Falabella, M., Fernandez, R. J., Johnson, F. B., & Kaufman, B. A. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666180228165527 · Cited by 98 · see citing works
When Genome Maintenance Goes Badly Awry
Kass, E. M., Moynahan, M. E., & Jasin, M. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.05.021 · Cited by 83 · see citing works
“New strategies are also being developed, including one that targets a specific defect incurred by BRCA1/2 mutant cells when replicating through DNA structures (Zimmer et al., 2016).”
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 · see citing works
“The G4 DNA is thought to play roles in various cellular processes including transcriptional activation, stimulation of meiotic recombination, chromatin assembly and rudimentary telomere capping[32, 33].”
BackgroundModeling Therapy Resistance in BRCA1/2 -Mutant Cancers
Dréan, A., Williamson, C. T., Brough, R., Brandsma, I., Menon, M. R., Konde, A., García-Murillas, I., Pemberton, H. N., Frankum, J. R., Rafiq, R., et al. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0098 · Cited by 87 · see citing works
“BRCA2 (29,30), to validate these observations.”
BRCA2 functions: from DNA repair to replication fork stabilization
Fradet‐Turcotte, A., Sitz, J., Grapton, D., & Orthwein, A. (2016) · Endocrine Related Cancer · doi:10.1530/erc-16-0297 · Cited by 82 · see citing works
“Consistent with the ability of this molecule to stabilize replication roadblocks, PSD leads to replication stress in cells depleted in BRCA1 or RAD51 (Zimmer et al. 2016).”
BackgroundInfluentialBeauvarlet, 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 · see citing works
“In the latter study, inhibition of DNA repair using a PARP inhibitor enhanced the antitumor effect of G4 ligand RHPS4 in vitro and in tumor xenografts (51).”
BackgroundG-quadruplex in cancer biology and drug discovery
Nakanishi, C., & Seimiya, H. (2020) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2020.03.178 · Cited by 91 · see citing works
Treatment of Ovarian Cancer Beyond PARP Inhibition: Current and Future Options
Garg, V., & Oza, A. M. (2023) · Drugs · doi:10.1007/s40265-023-01934-0 · Cited by 69 · see citing works
“G4-induced genomic instability has been linked to carcinogenesis, although synthetic lethality in this context is being explored as a therapeutic target in HRD cancers [164].”
BackgroundRecent advances on G-quadruplex for biosensing, bioimaging and cancer therapy
Xu, J., Jiang, R., He, H.-L., Ma, C.-B., & Tang, Z.-W. (2021) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2021.116257 · Cited by 69 · see citing works
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On the Road to Fight Cancer: The Potential of G-Quadruplex Ligands as Novel Therapeutic Agents
Alessandrini, I., Recagni, M., Zaffaroni, N., & Folini, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115947 · Cited by 83 · see citing works
“The exposure of ALT-positive osteosarcoma cells to Tetra-Pt(bpy) inhibited the strand invasion/annealing step of telomeric homologous recombination (HR) thus resulting in reduced telomere sister chromatin exchanges as well as in a decrease in the number of telomere-localized RPA and RAD51 foci, which indicate a reduct…”
BackgroundInfluentialYang, D. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9666-7_1 · Cited by 76 · see citing works
RNF168 regulates R-loop resolution and genomic stability in BRCA1/2-deficient tumors.
Patel, P. S., Abraham, K., Guturi, K. K. N., Halaby, M., Khan, Z., Palomero, L., Ho, B., Duan, S., St-Germain, J., Algouneh, A., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci140105 · Cited by 64
“Exposed ssDNA in R-loops can form G4 structures, DNA secondary structures that can act as barriers to fork progression and promote genomic instability (40).”
BackgroundBRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity
Tacconi, E. M., Lai, X., Folio, C., Porru, M., Zonderland, G., Badie, S., Michl, J., Sechi, I., Rogier, M., Matía, V., et al. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201607446 · Cited by 69 · see citing works
“The shRNAs targeting human BRCA1 (AGT ATG CAA ACA GCT ATA AT) or BRCA2 (GGG AAA CAC TCA GAT TAA A (Zimmer et al, 2016)) were cloned into pLKOTetOn and constructs were introduced into H1299 cells using lentiviral infection.”
InfluentialSelf-citationThe Hammer and the Dance of Cell Cycle Control
Παναγόπουλος, Α., & Altmeyer, M. (2020) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2020.11.002 · Cited by 70 · see citing works
G-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
The Relevance of G-Quadruplexes for DNA Repair
Linke, R., Limmer, M., Juranek, S., Heine, A., & Paeschke, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212599 · Cited by 64 · see citing works
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
Rescue from replication stress during mitosis
Fragkos, M., & Naim, V. (2017) · Cell Cycle · doi:10.1080/15384101.2017.1288322 · Cited by 60 · see citing works
The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF8
Singh, A. N., Oehler, J., Torrecilla, I., Kilgas, S., Li, S., Vaz, B., Guérillon, C., Fielden, J., Hernández-Carralero, E., Cabrera, E., et al. (2019) · The EMBO Journal · doi:10.15252/embj.2019102361 · Cited by 61 · see citing works
Self-citationHERC2 Facilitates BLM and WRN Helicase Complex Interaction with RPA to Suppress G-Quadruplex DNA
Wu, W., Rokutanda, N., Takeuchi, J., Lai, Y., Maruyama, R., Togashi, Y., Nishikawa, H., Arai, N., Miyoshi, Y., Suzuki, N., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-1877 · Cited by 57 · see citing works
Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells
Groelly, F. J., Dagg, R. A., Petropoulos, M., Rossetti, G. G., Prasad, B., Παναγόπουλος, Α., Paulsen, T., Karamichali, A., Jones, S. E., Ochs, F., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.07.011 · Cited by 58 · see citing works
“The H1299 cells used in this study carry a doxycycline (DOX)-inducible short hairpin RNA (shRNA) againstBRCA2 (Zimmer et al., 2016), which enables the effective inhibition of BRCA2 expression after 48 h of DOX treatment (Figure S1A).”
BackgroundSelf-citationDNA damage processing at telomeres: The ends justify the means
Fouquerel, E., Parikh, D., & Opresko, P. L. (2016) · DNA repair · doi:10.1016/j.dnarep.2016.05.022 · Cited by 48 · see citing works
The 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
Detection of alternative DNA structures and its implications for human disease
Matos-Rodrigues, G. E., Hisey, J. A., Nussenzweig, A., & Mirkin, S. M. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.08.018 · Cited by 65 · see citing works
Ligands stimulating antitumour immunity as the next G-quadruplex challenge
Miglietta, G., Marinello, J., Russo, M., & Capranico, G. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01649-y · Cited by 44 · 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].”
BackgroundERCC1/XPF Is Important for Repair of DNA Double-Strand Breaks Containing Secondary Structures
Li, S., Lu, H., Wang, Z., Hu, Q., Wang, H., Xiang, R., Chiba, T., & Wu, X. (2019) · iScience · doi:10.1016/j.isci.2019.05.017 · Cited by 40 · see citing works
“It has been shown that G4-stabilizing compounds can selectively eliminate HR-compromised tumors, including those with a BRCA1 or BRCA2 deficiency (Zimmer et al., 2016).”
BackgroundOkazaki fragment maturation: DNA flap dynamics for cell proliferation and survival
Sun, H., Ma, L., Tsai, Y.-F., Abeywardana, T., Shen, B., & Zheng, L. (2022) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.06.014 · Cited by 48 · see citing works
de Krijger, I., Boersma, V., & Jacobs, J. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2021.04.002 · Cited by 40 · see citing works
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Porro, A., Berti, M., Pizzolato, J., Bologna, S., Kaden, S., Saxer, A., Ma, Y., Nagasawa, K., Sartori, A. A., & Jiricny, J. (2017) · Nature Communications · doi:10.1038/s41467-017-01074-6 · Cited by 47 · see citing works
Lefebvre, J., Guetta, C., Poyer, F., Mahuteau‐Betzer, F., & Teulade‐Fichou, M. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201703783 · Cited by 58 · see citing works
PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA
Day, T. A., Layer, J. V., Cleary, J. P., Guha, S., Stevenson, K. E., Tivey, T. R., Kim, S. S., Schinzel, A. C., Izzo, F., Doench, J. G., et al. (2017) · Nature Communications · doi:10.1038/ncomms15110 · Cited by 42 · see citing works
Masai, H., & Tanaka, T. (2020) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2020.05.132 · Cited by 50 · see citing works
“PDS induces DSB accumulation, checkpoint activation, and deregulated G2/M progression and enhances the replication defect intrinsic to HR deficiency therapeutic potential of G4stabilizing ligand to selectively eliminate HRcompromised cells and tumors, including those resistant to PARP inhibition [95]”
BackgroundInfluentialThe Helicase PIF1 Facilitates Resection over Sequences Prone to Forming G4 Structures.
Jimeno, S., Camarillo, R., Mejías-Navarro, F., Fernández-Ávila, M. J., Soria-Bretones, I., Prados-Carvajal, R., & Huertas, P. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.12.029 · Cited by 39
“Interestingly, a recent study has shown that BRCA1 depletion causes sensitivity to pyridostatin (Xu et al., 2017; Zimmer et al., 2016).”
BackgroundAnti‐tumoural activity of the G‐quadruplex ligand pyridostatin against BRCA1/2‐deficient tumours
Groelly, F. J., Porru, M., Zimmer, J., Benainous, H., Visser, Y. D., Kosova, A. A., Vito, S. D., Serra, V., Ryan, A. J., Leonetti, C., et al. (2022) · EMBO Molecular Medicine · doi:10.15252/emmm.202114501 · Cited by 41 · see citing works
Self-citationDNA 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
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Self-citationHillmann, J. S., Maass, N., Bauerschlag, D., & Flörkemeier, I. (2025) · BMC Medicine · doi:10.1186/s12916-024-03826-w · Cited by 35 · see citing works
Beyond Kinases: Targeting Replication Stress Proteins in Cancer Therapy
Baillie, K. E., & Stirling, P. C. (2020) · Trends in cancer · doi:10.1016/j.trecan.2020.10.010 · Cited by 40 · see citing works
G-quadruplexes in cancer-related gene promoters: from identification to therapeutic targeting
Romano, F., Porzio, A. D., Iaccarino, N., Riccardi, G., Lorenzo, R. D., Laneri, S., Pagano, B., Amato, J., & Randazzo, A. (2023) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2023.2271168 · Cited by 41 · see citing works
“Another correlation with G4s is represented by activation of PARP enzymes upon treatment with a G4 ligand [342,343].”
BackgroundDuskova, K., Lejault, P., Benchimol, É., Guillot, R., Britton, S., Granzhan, A., & Monchaud, D. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.9b11150 · Cited by 47 · see citing works
Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer
Telli, M. L., Stover, D. G., Loi, S., Aparicio, S. A. J. R., Carey, L., Domchek, S. M., Newman, L. A., Sledge, G. W., & Winer, E. P. (2018) · Breast Cancer Research and Treatment · doi:10.1007/s10549-018-4807-x · Cited by 45 · see citing works
DDX11 loss causes replication stress and pharmacologically exploitable DNA repair defects
Jegadesan, N. K., & Branzei, D. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2024258118 · Cited by 34 · see citing works
“We found that double mutants between DDX11 KO and either si BRCA1 or si BRCA2 are more sensitive than single mutants toward olaparib, cisplatin, and G4 stabilizing drugs, such as Pyr-idostatin and Telomestatin, shown previously to sensitize DDX11 and BRCA1/2 mutant cells (8, 30) (Fig.”
Zuo1 supports G4 structure formation and directs repair toward nucleotide excision repair
Magis, A. D., Götz, S., Hajikazemi, M., Fekete-Szücs, E., Caterino, M., Juranek, S., & Paeschke, K. (2020) · Nature Communications · doi:10.1038/s41467-020-17701-8 · Cited by 53 · see citing works
From R-Loops to G-Quadruplexes: Emerging New Threats for the Replication Fork
Maffia, A., Ranise, C., & Sabbioneda, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041506 · Cited by 40 · see citing works
Diagnosis and treatment of ALT tumors: is Trabectedin a new therapeutic option?
Pompili, L., Leonetti, C., Biroccio, A., & Salvati, E. (2017) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-017-0657-3 · Cited by 34 · see citing works
“As explained above, longer telomeres and the high recombination frequency, also increased by TERRA transcripition, are consistent with a higher replication stress, telomeric fragile sites, DNA-RNA hybrids (R-loops) and secondary structures (G-quadruplexes).”
InfluentialSelf-citationAdvances in cGAS-STING Signaling Pathway and Diseases
Yang, Y., Huang, Y., & Zeng, Z. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.800393 · Cited by 30 · see citing works
Positive and negative regulators of RAD51/DMC1 in homologous recombination and DNA replication
Ito, M., Fujita, Y., & Shinohara, A. (2023) · DNA repair · doi:10.1016/j.dnarep.2023.103613 · Cited by 40 · see citing works
Chlorambucil targets BRCA1/2‐deficient tumours and counteracts PARP inhibitor resistance
Tacconi, E. M., Badie, S., Gregoriis, G. D., Reisländer, T., Lai, X., Porru, M., Folio, C., Moore, J., Kopp, A., Torres, J. B., et al. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201809982 · Cited by 38 · see citing works
“In contrast, BRCA2-deficient cells, with intrinsic defects in replication fork progression and stability (Zimmer et al, 2016), showed detectable levels of RPA Ser33 phosphorylation even in the absence of any treatment (0 h), and these were markedly increased upon incubation with 1 lM chlorambucil…”
BackgroundInfluentialSelf-citationCancer-associated mutations in the iron-sulfur domain of FANCJ affect G-quadruplex metabolism
Odermatt, D. C., Lee, W. T. C., Wild, S., Jóźwiakowski, S. K., Rothenberg, E., & Gari, K. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1008740 · Cited by 33 · see citing works
Duskova, K., Lamarche, J., Amor, S., Caron, C., Queyriaux, N., Gaschard, M., Penouilh, M., Robillard, G., Delmas, D., Devillers, C. H., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01978 · Cited by 36 · see citing works
Heme oxygenase-1 protects cells from replication stress
Chudy, P., Kochan, J. A., Wawro, M., Nguyen, P., Gorczyca, M. E., Varanko, A., Retka, A., Ghadei, S. S., Napieralska, E., Grochot‐Przeczek, A., et al. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103247 · Cited by 30 · see citing works
“Indeed, administration of small molecules stabilizing G-quadruplexes slowed down DNA replication and stalled replication forks [13].”
BackgroundMutSβ regulates G4-associated telomeric R-loops to maintain telomere integrity in ALT cancer cells
Sakellariou, D., Bak, S. T., Işık, E., Barroso, S. I., Porro, A., Aguilera, A., Bártek, J., Janščák, P., & Peña-Dı́az, J. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110602 · Cited by 33 · see citing works
Breast Cancer Predisposition Genes and Synthetic Lethality
Neiger, H. E., Siegler, E. L., & Shi, Y. H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115614 · Cited by 33 · see citing works
Crossroads of telomere biology and anticancer drug discovery
Seimiya, H. (2020) · Cancer Science · doi:10.1111/cas.14540 · Cited by 28 · see citing works
Ubiquitin-mediated DNA damage response is synthetic lethal with G-quadruplex stabilizer CX-5461
Masud, T., Soong, C., Xu, H., Biele, J., Bjornson, S., McKinney, S., & Aparicio, S. (2021) · Scientific Reports · doi:10.1038/s41598-021-88988-w · Cited by 27 · see citing works
BMPQ-1 binds selectively to (3+1) hybrid topologies in human telomeric G-quadruplex multimers
Gao, C., Liu, Z., Hou, H., Ding, J., Chen, X., Xie, C., Song, Z., Hu, Z., Feng, M.-Q., Mohamed, H. I., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa870 · Cited by 26
“The telomere dysfunction coming from the G-quadruplex ligands can lead to phenomena similar to that of DNA damage in eliciting cell cycle arrest and apoptosis (48).”
BackgroundObi, I. R., Rentoft, M., Singh, V., Jamroškovič, J., Chand, K., Chorell, E., Westerlund, F., & Sabouri, N. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa820 · Cited by 30 · see citing works
“For instance pyridostatin, a small G4-stabilizing molecule, inhibits telomerase activity in vitro (34), slows replication fork progression (35) and elevates the levels of -H2AX, a marker of DNA damage, in human cells (36).”
BackgroundLee, H.-S., Carmena, M., Liskovykh, M., Peat, E., Kim, J.-H., Oshimura, M., Masumoto, H., Teulade-Fichou, M., Pommier, Y., Earnshaw, W. C., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-0894 · Cited by 26
“It is worth noting that we cannot exclude additional mechaisms of action for these G4 ligands such as transcriptional inactivation of genes important for chromosome segregation or induction of chromosomal DSBs as previously was described for other G4 stabilizers (21,48,49).”
BackgroundTelomere Targeting Approaches in Cancer: Beyond Length Maintenance
Vertecchi, E., Rizzo, A., & Salvati, E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073784 · Cited by 25 · see citing works
“Pyridostatin G-quadruplex i-motifs DDR activation BRCA1/2 mut Colon cancer Renal cancer [88,89]”
BackgroundAn emerging picture of FANCJ’s role in G4 resolution to facilitate DNA replication
Brosh, R. M., & Wu, Y. (2021) · NAR Cancer · doi:10.1093/narcan/zcab034 · Cited by 23 · see citing works
“Indeed, BRCA1or BRCA2-deficient cancer cells are hypersensitive to ligands that bind to and stabilize G4 DNA structures (85).”
Background
- Authors
- Zimmer, J., Tacconi, E. M. C., Folio, C., Badie, S., Porru, M., Klare, K., Tumiati, M., Markkanen, E., Halder, S., Ryan, A., Jackson, S. P., Ramadan, K., Kuznetsov, S. G., Biroccio, A., Sale, J. E., & Tarsounas, M.
- Affiliations
- University of Oxford (GB)
- Instituto Nazionale Tumori Regina Elena (IT)
- University of Helsinki (FI)
- University of Cambridge (GB)
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Tarsounas, Madalena
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 61
- Issue
- 3
- Pages
- 449-460
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4747901
- OpenAlex
- W2207187217
- Cited by
- 261
- References
- 58
- Citations by year
- 2026: 13 · 2025: 24 · 2024: 32 · 2023: 28 · 2022: 22 · 2021: 37 · 2020: 33 · 2019: 25 · 2018: 16 · 2017: 22 · 2016: 9
- FWCI
- 6.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Molecular Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Wellcome Trust (WT092096, 092096)
- Cancer Research UK (17201, 18796, S_3001, 11224)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (141197)
- Medical Research Council (MC_PC_12001/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- G-quadruplex, BRCA1, BRCA2, homologous recombination deficiency, telomere replication, telomere instability, pyridostatin, DNA damage checkpoint, G2/M transition, olaparib resistance, 53BP1, REV7, PARP inhibitor resistance, replication fork collapse
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Tumor Suppressor p53-Binding Protein 1, Aminoquinolines, Animals, Antineoplastic Agents, Dose-Response Relationship, Drug, Humans, Male, Mice, Nude, Neoplasms, Picolinic Acids, Time Factors, Transfection, Biomarkers, Tumor, Telomere, Drug Resistance, Neoplasm, BRCA1 Protein, Xenograft Model Antitumor Assays, BRCA2 Protein, RNA Interference, Tumor Burden, Intracellular Signaling Peptides and Proteins, Cell Proliferation, DNA Breaks, Double-Stranded, G-Quadruplexes, HEK293 Cells, Molecular Targeted Therapy, G2 Phase Cell Cycle Checkpoints, Mad2 Proteins
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