Small-molecule–induced DNA damage identifies alternative DNA structures in human genes
Open accessAbstract
Guanine-rich DNA sequences that can adopt non-Watson-Crick structures in vitro are prevalent in the human genome. Whether such structures normally exist in mammalian cells has, however, been the subject of active research for decades. Here we show that the G-quadruplex-interacting drug pyridostatin promotes growth arrest in human cancer cells by inducing replication- and transcription-dependent DNA damage. A chromatin immunoprecipitation sequencing analysis of the DNA damage marker γH2AX provided the genome-wide distribution of pyridostatin-induced sites of damage and revealed that pyridostatin targets gene bodies containing clusters of sequences with a propensity for G-quadruplex formation. As a result, pyridostatin modulated the expression of these genes, including the proto-oncogene SRC. We observed that pyridostatin reduced SRC protein abundance and SRC-dependent cellular motility in human breast cancer cells, validating SRC as a target of this drug. Our unbiased approach to define genomic sites of action for a drug establishes a framework for discovering functional DNA-drug interactions.
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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 [26]
The Results section (‘Transcription- and replication-dependent DNA damage’; page unavailable) shows that pyridostatin, a G-quadruplex-binding drug, induces DNA damage in treated cells. That supports a link between targeting G-quadruplexes and DNA damage, but it does not establish that deregulated G4 formation is a major driver of genomic instability generally. (LLM, conf=0.86)
Experimental — accuracy not yet measuredError-prone polymerases might be engaged at slowed or stalled replication forks to ensure complete G4 replication, as specialized polymerases like eta, kappa, and Rev1 are essential for G4 stability, further increasing the density of localized genomic damages.
“Error-prone polymerases might be engaged at slowed or stalled replication forks to ensure complete G4 replication, as specialized polymerases like eta, kappa, and Rev1 are essential for G4 stability – further increasing the density of localized genomic damages (26,78–80).”
From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [26]
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“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).”
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Genome-wide mapping of G-quadruplex structures with CUT&Tag
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G-Quadruplex: A Regulator of Gene Expression and Its Chemical Targeting
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Transcriptome-wide identification of transient RNA G-quadruplexes in human cells
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G quadruplexes are genomewide targets of transcriptional helicases XPB and XPD
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Thioflavin T as an efficient fluorescence sensor for selective recognition of RNA G-quadruplexes
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Visualizing biologically active small molecules in cells using click chemistry
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Small-molecule quadruplex-targeted drug discovery
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Selective RNA Versus DNA G‐Quadruplex Targeting by In Situ Click Chemistry
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Self-citationG-Quadruplex DNA as a Molecular Target for Induced Synthetic Lethality in Cancer Cells
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Self-citationG4LDB: a database for discovering and studying G-quadruplex ligands
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Ligand Design to Acquire Specificity to Intended G‐Quadruplex Structures
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G‐Quadruplex Structures and Their Interaction Diversity with Ligands
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Chemical profiling of DNA G-quadruplex-interacting proteins in live cells
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Self-citationDSBCapture: in situ capture and sequencing of DNA breaks
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FANCJ promotes DNA synthesis through G‐quadruplex structures
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Interplay of Guanine Oxidation and G-Quadruplex Folding in Gene Promoters
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Self-citationG-quadruplex DNA structure is a positive regulator of MYC transcription
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G-Quadruplexes and Their Ligands: Biophysical Methods to Unravel G-Quadruplex/Ligand Interactions
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- Authors
- Rodriguez, R., Miller, K. M., Forment, J. V., Bradshaw, C. R., Nikan, M., Britton, S., Oelschlaegel, T., Xhemalce, B., Balasubramanian, S., & Jackson, S. P.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Balasubramanian, Shankar
- Jackson, Stephen P
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2012-02-05
- Volume
- 8
- Issue
- 3
- Pages
- 301-310
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC3433707
- OpenAlex
- W2042374693
- Cited by
- 741
- References
- 50
- Citations by year
- 2026: 35 · 2025: 55 · 2024: 66 · 2023: 53 · 2022: 41 · 2021: 60 · 2020: 58 · 2019: 56 · 2018: 52 · 2017: 52 · 2016: 39 · 2015: 54 · 2014: 49 · 2013: 44 · 2012: 27
- FWCI
- 22.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (092096/Z/10/Z, 086861/Z/08/Z, 086861, 092096)
- Cancer Research UK (11961, C6/A11224, 11224, A11224, C9681/A11961)
- Biotechnology and Biological Sciences Research Council (BB/G008337/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- pyridostatin, G-quadruplex, alternative DNA structures, DNA damage, γH2AX, cell cycle arrest, breast cancer, guanine-rich DNA, gene expression regulation, drug-DNA interaction, ChIP-seq
- MeSH terms
- Proto-Oncogene Mas, Aminoquinolines, Antineoplastic Agents, Breast Neoplasms, Cell Cycle, DNA, DNA Damage, Drug Screening Assays, Antitumor, Humans, Molecular Weight, Picolinic Acids, Structure-Activity Relationship, Tumor Cells, Cultured, Cell Proliferation, G-Quadruplexes
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