Ligand-Dependent Enhancer Activation Regulated by Topoisomerase-I Activity
| Autor: | Wenbo Li, Jie Zhang, Piotr Kozbial, Kenneth A. Ohgi, Yuliang Tan, Janusz Puc, Zhijie Liu, Aneel K. Aggarwal, Tom Suter, Michael G. Rosenfeld |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
DNA Repair
Transcription Genetic Cell Type I Enhancer RNAs Medical and Health Sciences Androgen chemistry.chemical_compound 0302 clinical medicine Single-Stranded Transcription (biology) Receptors Cancer MRE11 Homologue Protein 0303 health sciences Tumor biology Biological Sciences Ligand (biochemistry) Cell biology 3. Good health DNA-Binding Proteins Enhancer Elements Genetic medicine.anatomical_structure DNA Topoisomerases Type I Receptors Androgen Gene Knockdown Techniques 030220 oncology & carcinogenesis Transcription Enhancer Elements DNA repair 1.1 Normal biological development and functioning General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences Rare Diseases Genetic Underpinning research Cell Line Tumor Genetics medicine Humans DNA Breaks Single-Stranded Enhancer Transcription factor 030304 developmental biology Homeodomain Proteins Biochemistry Genetics and Molecular Biology(all) Topoisomerase DNA Breaks Molecular biology body regions Gene Expression Regulation MRN complex chemistry biology.protein DNA Topoisomerases 030217 neurology & neurosurgery DNA Developmental Biology Transcription Factors |
| Zdroj: | Cell, vol 160, iss 3 |
| ISSN: | 0092-8674 |
| DOI: | 10.1016/j.cell.2014.12.023 |
| Popis: | SummaryThe discovery that enhancers are regulated transcription units, encoding eRNAs, has raised new questions about the mechanisms of their activation. Here, we report an unexpected molecular mechanism that underlies ligand-dependent enhancer activation, based on DNA nicking to relieve torsional stress from eRNA synthesis. Using dihydrotestosterone (DHT)-induced binding of androgen receptor (AR) to prostate cancer cell enhancers as a model, we show rapid recruitment, within minutes, of DNA topoisomerase I (TOP1) to a large cohort of AR-regulated enhancers. Furthermore, we show that the DNA nicking activity of TOP1 is a prerequisite for robust eRNA synthesis and enhancer activation and is kinetically accompanied by the recruitment of ATR and the MRN complex, followed by additional components of DNA damage repair machinery to the AR-regulated enhancers. Together, our studies reveal a linkage between eRNA synthesis and ligand-dependent TOP1-mediated nicking—a strategy exerting quantitative effects on eRNA expression in regulating AR-bound enhancer-dependent transcriptional programs. |
| Databáze: | OpenAIRE |
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