Active chromatin DNA

Active chromatin DNA in tumor cells refers to the transcriptionally accessible regions of the genome, primarily euchromatin, which are often expanded or dysregulated to drive oncogenic programs. These regions are characterized by high levels of histone acetylation (e.g., H3K27ac) and the presence of super-enhancers or extrachromosomal DNA (ecDNA), which provide a structural basis for high-level gene expression (Wu et al., 2019, Nature). Unlike bulk genomic DNA, active chromatin is physically more accessible to small molecules, allowing for the development of drugs that selectively disrupt transcription in cancer cells. Agents such as lurbinectedin and trabectedin bind to the minor groove within these active regions, leading to the stalling of RNA polymerase II and the induction of transcription-coupled DNA damage (Singh et al., 2021, Drugs). This targeting strategy exploits the transcriptional addiction of many cancers, particularly those driven by potent oncogenes like MYC. However, therapeutic challenges include the potential for systemic toxicity due to the inhibition of essential transcription in normal cells, necessitating careful patient selection using biomarkers like ATAC-seq or epigenetic profiling.

Other names

EuchromatinOpen chromatinAccessible DNATranscriptionally active DNAActive genomic DNA

Drugs targeting active chromatin DNA typically bind to the minor groove or intercalate into open DNA regions, leading to the displacement of transcription factors, inhibition of RNA polymerase II, and the induction of transcription-coupled DNA double-strand breaks (Singh et al., 2021, Drugs; D'Incalci & Galmarini, 2010, Mol Cancer Ther).