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G4-ligand-conjugated oligonucleotides mediate selective binding and stabilization of individual G4 DNA structures
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0001-6347-2169
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2023 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 146, no 10, p. 6926-6935Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) DNA structures are prevalent secondary DNA structures implicated in fundamental cellular functions, such as replication and transcription. Furthermore, G4 structures are directly correlated to human diseases such as cancer and have been highlighted as promising therapeutic targets for their ability to regulate disease-causing genes, e.g., oncogenes. Small molecules that bind and stabilize these structures are thus valuable from a therapeutic perspective and helpful in studying the biological functions of the G4 structures. However, there are hundreds of thousands of G4 DNA motifs in the human genome, and a long-standing problem in the field is how to achieve specificity among these different G4 structures. Here, we developed a strategy to selectively target an individual G4 DNA structure. The strategy is based on a ligand that binds and stabilizes G4s without selectivity, conjugated to a guide oligonucleotide, that specifically directs the G4-Ligand-conjugated oligo (GL-O) to the single target G4 structure. By employing various biophysical and biochemical techniques, we show that the developed method enables the targeting of a unique, specific G4 structure without impacting other off-target G4 formations. Considering the vast amount of G4s in the human genome, this represents a promising strategy to study the presence and functions of individual G4s but may also hold potential as a future therapeutic modality.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2023. Vol. 146, no 10, p. 6926-6935
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:umu:diva-222294DOI: 10.1021/jacs.3c14408ISI: 001179314400001PubMedID: 38430200Scopus ID: 2-s2.0-85186374110OAI: oai:DiVA.org:umu-222294DiVA, id: diva2:1845788
Funder
The Kempe Foundations, JCK-3159The Kempe Foundations, SMK-1632The Kempe Foundations, SMK21-0059Swedish Research Council, 2017-05235Swedish Research Council, 2021-04805Swedish Research Council, 2018-0278Cancerforskningsfonden i Norrland, AMP19-968Knut and Alice Wallenberg Foundation, SMK21-0059Available from: 2024-03-20 Created: 2024-03-20 Last updated: 2024-03-20Bibliographically approved

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Berner, AndreasDas, Rabindra NathBhuma, NareshGolebiewska, JustynaAbrahamsson, AlvaAndréasson, MånsChaudhari, NamrataDoimo, MaraChand, KaramWanrooij, SjoerdChorell, Erik

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Berner, AndreasDas, Rabindra NathBhuma, NareshGolebiewska, JustynaAbrahamsson, AlvaAndréasson, MånsChaudhari, NamrataDoimo, MaraChand, KaramWanrooij, SjoerdChorell, Erik
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Department of Medical Biochemistry and BiophysicsDepartment of Chemistry
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Journal of the American Chemical Society
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

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