A Novel Small Molecule That Alters Shelterin Integrity and Triggers a DNA-Damage Response at Telomeres
Open accessAbstract
We describe a novel synthetic small molecule which shows an unprecedented stabilization of the human telomeric G-quadruplex with high selectivity relative to double-stranded DNA. We report that this compound can be used in vitro to inhibit telomerase activity and to uncap human POT1 (protection of telomeres 1) from the telomeric G-overhang. We also show that the small molecule G-quadruplex binder induces a partial alteration of shelterin through POT1 uncapping from telomeres in human HT1080 cancer cells and the presence of gammaH2AX foci colocalized at telomeres.
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Deregulated G4 formation is a major driver of genomic instability.
“there is strong evidence that deregulated G4-formation is a major driver of genomic instability”
From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [29]
In the paper’s main text (page unavailable), compound-induced stabilization of telomeric G-quadruplexes is linked to POT1 uncapping and a DNA-damage response in a human cancer cell line. That supports a specific route by which altered G4 formation can provoke damage signaling, but not the broader assertion that deregulated G4 formation is a major driver of genomic instability. (LLM, conf=0.85)
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Cites
Molecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints
Sancar, A., Lindsey-Boltz, L. A., Ünsal-Kaçmaz, K., & Linn, S. (2004) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.011303.073723 · Cited by 3,317 · see citing works
Shelterin: the protein complex that shapes and safeguards human telomeres
de Lange, T. (2005) · Genes & Development · doi:10.1101/gad.1346005 · Cited by 3,056 · see citing works
A DNA damage checkpoint response in telomere-initiated senescence
Fagagna, F. D. D., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., Saretzki, G., Carter, N. P., & Jackson, S. P. (2003) · Nature · doi:10.1038/nature02118 · Cited by 2,855 · see citing works
Living on a break: cellular senescence as a DNA-damage response
d'Adda di Fagagna, F. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2440 · Cited by 1,170 · see citing works
Flagged first, then by citations
Research works printed but not linked: 18
- [1]Sancer A Lindsey-Boltz LA Unsal-Kaçmaz K Linn S Annu. Rev. Biochem 2004 73 39 85 15189136
- [2]Liu D O'Connor MS Qin J Songyang Z J. Biol. Chem 2004 279 51338 51342 15383534
- [3](a) de Lange T Genes Dev 2005 19 2100 2110 16166375 (b) Palm W de Lange T Annu. Rev. Genet 2008 42 DOI: 10.1146/annurev.genet.41.110306. 130350 18680434 · DOI
- [4]Baumann P Cech TR Science 2001 292 1171 1175 11349150
- [5]Wang F Podell ER Zaug AJ Yang Y Baciu P Cech TR Lei M Nature 2007 445 506 510 17237768
- [6]Blackburn EH Cell 2001 106 661 673 11572773
- [7]Zahler AM Williamson JR Cech TR Prescott DM Nature 1991 350 718 720 2023635
- [8]Sun D Thompson B Cathers BE Salazar M Kerwin SM Trent JO Jenkins TC Neidle S Hurley LH J. Med. Chem 1997 40 2113 2116 9216827
- [9]De Cian A Lacroix L Douarre C Temime-Smaali N Trentesaux C Riou J-F Mergny J-L Biochimie 2008 90 131 155 17822826
- [10]De Cian A Cristofari G Reichenbach P De Lomos E Monchaud D Teulade-Fichou M-P Shin-ya K Lacroix L Lingner J Mergny J-L Proc. Natl. Acad. Sci. U.S.A 2007 104 17347 17352 17954919 PMC2077259
- [11]Gomez D Wenner T Brassert B Douarre C O'Donohue M-F El Khoury V Shin-ya K Morjani H Trentesaux C Riou J-F J. Biol. Chem 2006 281 38721 38729 17050546
- [12](a) Granotier C Pennarun G Riou L Hoffschir F Gauthier LR De Cian A Gomez D Mandine E Riou J-F Mergny J-L Mailliet P Dutrillaux B Boussin FD Nucleic Acids Res 2005 33 4182 4190 16052031 PMC1181860 (b) Jantos K Rodriguez R Ladame S Shirude PS Balasubramanian S J. Am. Chem. Soc 2006 128 13662 13663 17044674 PMC2195899 (c) Gonçalves DPN Rodriguez R Balasubramanian S Sanders JKM Chem. Commun 2006 4685 4687 PMC2220048 17109036 (d) Rodriguez R Pantosş GD Gonçalves DPN Sanders JKM Balasubramanian S Angew. Chem., Int. Ed 2007 46 5405 5407 PMC2277493 17562537 (e) Bejugam M Sewitz S Shirude PS Rodriguez R Shahid R Balasubramanian S J. Am. Chem. Soc 2007 129 12926 12927 17918848 PMC2195890 (f) Bugaut A Jantos K Wietor J-L Rodriguez R Sanders JKM Balasubramanian S Angew. Chem., Int. Ed 2008 47 2677 2680 PMC2408711 18300215 (g) Waller ZAE Shirude PS Rodriguez R Balasubramanian S Chem. Commun 2008 1467 1469 PMC2527513 18338058 (h) Fernando H Rodriguez R Balasubramanian S Biochemistry 2008 47 9365 9371 18702511 PMC2746966
- [13]Monchaud D Teulade-Fichou M-P Org. Biomol. Chem 2008 6 627 636 18264563
- [14]Mergny J-L Maurizot J-C ChemBioChem 2001 2 124 132 11828436
- [15]Shirude PS Gillies ER Ladame S Godde F Shin-ya K Huc I Balasubramanian S J. Am. Chem. Soc 2007 129 11890 11891 17845042 PMC2195897
- [16]Kieltyka R Englebienne P Fakhoury J Autexier C Moitessier N Sleiman HF J. Am. Chem. Soc 2008 130 10040 10041 18616250
- [17]Gomez D O'Donohue M-F Wenner T Douarre C Macadré J Koebel P Giraud-Panis M-J Kaplan H Kolkes A Shin-ya K Riou J-F Cancer Res 2006 66 6908 6912 16849533
- [19](a) d'Adda di Fagagna F Reaper PM Clay-Farrace L Fiegler H Carr P von Zglinicki T Saretzki G Carter NP Jackson SP Nature 2003 426 194 198 14608368 (b) d'Adda di Fagagna F Nat. Rev. Cancer 2008 8 512 522 18574463
Cited by
Sorted by citations
Small-molecule–induced DNA damage identifies alternative DNA structures in human genes
Rodriguez, R., Miller, K. M., Forment, J. V., Bradshaw, C. R., Nikan, M., Britton, S., Oelschlaegel, T., Xhemalce, B., Balasubramanian, S., & Jackson, S. P. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.780 · Cited by 741 · see citing works
Self-citationTargeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting Compounds
Zimmer, J., Tacconi, E. M. C., Folio, C., Badie, S., Porru, M., Klare, K., Tumiati, M., Markkanen, E., Halder, S., Ryan, A., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2015.12.004 · Cited by 261 · 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).”
BackgroundMethodLandscape 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
Self-citationElevated Levels of G-Quadruplex Formation in Human Stomach and Liver Cancer Tissues
Biffi, G., Tannahill, D., Miller, J., Howat, W. J., & Balasubramanian, S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0102711 · Cited by 223 · see citing works
“For example, G-quadruplex stabilization by a small molecule can repress transcription of certain oncogenes and/or induce DNA damage at telomeres and oncogenes leading to replication defects and cell death [10–17].”
BackgroundSelf-citationBossaert, M., Pipier, A., Riou, J.-F., Noirot, C., Nguyên, L.-T., Serre, R.-F., Bouchez, O., Defrancq, E., Calsou, P., Britton, S., et al. (2021) · eLife · doi:10.7554/elife.65184 · Cited by 97 · see citing works
“To investigate whether CX-5461 resistance induced by TOP2A mutations extends to other G4 stabilizers, we tested CXR mutants for their cross-resistance to pyridostatin (PDS), one of the best characterized G4 ligands so far (Rodriguez et al., 2008).”
BackgroundSelf-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
- Authors
- Rodriguez, R., Müller, S., Yeoman, J. A., Trentesaux, C., Riou, J.-F., & Balasubramanian, S.
- Affiliations
- Inserm (FR)
- Corresponding author
- Riou, Jean-François
- Balasubramanian, Shankar
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2008-11-01
- Volume
- 130
- Issue
- 47
- Pages
- 15758-15759
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC2746963
- OpenAlex
- W2035030010
- Cited by
- 517
- References
- 4
- Citations by year
- 2026: 25 · 2025: 40 · 2024: 53 · 2023: 34 · 2022: 36 · 2021: 51 · 2020: 43 · 2019: 31 · 2018: 26 · 2017: 29 · 2016: 20 · 2015: 26 · 2014: 30 · 2013: 23 · 2012: 20
- FWCI
- 6.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research UK (A5709)
- Biotechnology and Biological Sciences Research Council
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
- Keywords
- small molecules, G-quadruplex stabilization, telomeres, shelterin, telomerase inhibition, DNA damage response, γH2AX foci, HT1080 cells, telomere protection
- MeSH terms
- Shelterin Complex, DNA Damage, Humans, Molecular Structure, Telomere, Telomere-Binding Proteins, Cell Line, Tumor
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