Cited by 747DNA and Nucleic Acid ChemistryMetal complexes synthesis and propertiesEpigenetics and DNA Methylation

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Small-molecule–induced DNA damage identifies alternative DNA structures in human genes

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Rodriguez, Raphaël, Miller, Kyle M, Forment, Josep V, Bradshaw, Charles R, Nikan, Mehran, Britton, Sébastien, Oelschlaegel, Tobias, Xhemalce, Blerta, Balasubramanian, Shankar, Jackson, Stephen P·2012·Nature Chemical Biology

DOI 10.1038/nchembio.780PMC PMC3433707

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Abstract

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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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: Rodriguez, Raphaël
Miller, Kyle M
Forment, Josep V
Bradshaw, Charles R
Nikan, Mehran
Britton, Sébastien
Balasubramanian, Shankar
Venue: Nature Chemical Biology
Publisher: Springer Science and Business Media LLC
Published: 2012-02-05
Volume: 8
Issue: 3
Pages: 301-310
ISSN: 1552-4450 (ISSN-L)
1552-4469
DOI: 10.1038/nchembio.780
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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Small-molecule–induced DNA damage identifies alternative DNA structures in human genes

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