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DNA damage and genome instability by G-quadruplex ligands are mediated by R loops in human cancer cells

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De Magis, Alessio, Manzo, Stefano G., Russo, Marco, Marinello, Jessica, Morigi, Rita, Sordet, Olivier, Capranico, Giovanni·2019·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1810409116PMC PMC6338839
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Abstract

G quadruplexes (G4s) and R loops are noncanonical DNA structures that can regulate basic nuclear processes and trigger DNA damage, genome instability, and cell killing. By different technical approaches, we here establish that specific G4 ligands stabilize G4s and simultaneously increase R-loop levels within minutes in human cancer cells. Genome-wide mapping of R loops showed that the studied G4 ligands likely cause the spreading of R loops to adjacent regions containing G4 structures, preferentially at 3′-end regions of expressed genes, which are partially ligand-specific. Overexpression of an exogenous human RNaseH1 rescued DNA damage induced by G4 ligands in BRCA2 -proficient and BRCA2 -silenced cancer cells. Moreover, even if the studied G4 ligands increased noncanonical DNA structures at similar levels in nuclear chromatin, their cellular effects were different in relation to cell-killing activity and stimulation of micronuclei, a hallmark of genome instability. Our findings therefore establish that G4 ligands can induce DNA damage by an R loop-dependent mechanism that can eventually lead to different cellular consequences depending on the chemical nature of the ligands.

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Crossref · 10.1073/pnas.1810409116

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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 [27]

    The Abstract says that stabilization of G4s by specific ligands or genetic defects can lead to genome instability. The Discussion reports an R-loop-dependent mechanism in human cancer cells treated with the studied G4 ligands. These passages support a link, but do not establish that deregulated G4 formation is a major driver of genomic instability generally. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • More serious DNA damages, such as double-strand breaks associated with non-B DNA structures like G4s, and the subsequent DNA repair can be mutagenic.

    “Lastly, more serious DNA damages, such as double-strand breaks associated with non-B DNA structures like G4s, and the subsequent DNA repair can be mutagenic (7,27).”

    From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [27]

    The Results (page not available) report that G4 ligands induce double-strand breaks and that PDS-induced breaks can lead to micronuclei, a hallmark of genome instability. The paper does not show that subsequent DNA repair is mutagenic; it instead links micronuclei to breaks that fail to be properly repaired. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • One well-documented mechanism for G4-mediated genomic instability involves G4-enhanced formation of R-loops that can spread into adjacent regions containing G4s.

    “While not exclusively resulting in point-mutations, one well-documented mechanism for G4-mediated genomic instability involves G4-enhanced formation of R-loops, that can spread into adjacent regions containing G4s (27).”

    From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [27]

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Authors
De Magis, A., Manzo, S. G., Russo, M., Marinello, J., Morigi, R., Sordet, O., & Capranico, G.
Affiliations
  • Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy;
  • University of Bologna (IT)
  • Centre National de la Recherche Scientifique (FR)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2018-12-27
Volume
116
Issue
3
Pages
816-825
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1810409116
PMC
PMC6338839
OpenAlex
W2907750653
Cited by
332
References
7
Citations by year
2026: 29 · 2025: 33 · 2024: 61 · 2023: 48 · 2022: 45 · 2021: 69 · 2020: 36 · 2019: 11
FWCI
10.32
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/aboutpnas/licenses.xhtml (vor, 182 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
Funders
Associazione Italiana per la Ricerca sul Cancro (IG-15886)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
G-quadruplex ligands, R-loops, DNA damage, genomic instability, non-canonical DNA structures, RNase H1, BRCA2, micronuclei, cancer cells, ligand specificity
MeSH terms
Aminoquinolines, DNA Damage, Humans, Ligands, Neoplasms, Picolinic Acids, Genes, BRCA2, Genomic Instability, Cell Line, Tumor, G-Quadruplexes

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