Small molecule-induced DNA damage identifies alternative DNA structures in human genes
By Raphaël Rodriguez, K. Miller, J. Forment, Charles R. Bradshaw, Mehran Nikan, S. Britton, Tobias Oelschlaegel, Blerta Xhemalçe, Shankar Balasubramanian, Stephen P. Jackson. Nature Chemical Biology, 2012
676 citations recorded by the source corpus.
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 promoted growth arrest in human cancer cells via inducing replication- and transcription-dependent DNA damage. Chromatin immunoprecipitation sequence (ChIP-Seq) 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 levels and SRC-dependent cellular motility in human breast cancer cells, validating SRC as a target. Our unbiased approach to define genomic sites of action for a drug establishes a framework for discovering functional DNA-drug interactions.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/0698358637f23bb747c7e04da4bdfdf45c6c2647
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Citations in the corpus
- G-quadruplex structures mark human regulatory chromatin (2016, neutral): “To rule this out, we overlapped the high-confidence G4 ChIP–seq peak set (10,560) with the 10,560 most accessible FAIRE sites.”
- R loops: from transcription byproducts to threats to genome stability. (2012, neutral): “ChIP-seq analysis with antigH2AX antibodies provided evidence that pyridostatin targets G-clusters with tendency to form G-quadruplexes in active genes in human cells (Rodriguez et al., 2012).”
- The Structure and Function of DNA G-Quadruplexes (2020, positive): “lated protein that marks stand break sites, and is found to occur predominantly at predicted G4 regions of the cellular genome (Figure 3D) [47].”
- G-quadruplexes and their regulatory roles in biology (2015, neutral): “Chromatin immuno precipitation with an antibody directed against the DNA damage marker histone gamma H2AX identified genes enriched in pG4s (34).”