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Cell. 2015 Jan 29;160(3):367-80. doi: 10.1016/j.cell.2014.12.023. Epub 2015 Jan 22.

Ligand-dependent enhancer activation regulated by topoisomerase-I activity.

Author information

1
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0648, USA.
2
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0648, USA; Division of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093-0648, USA.
3
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0648, USA. Electronic address: mrosenfeld@ucsd.edu.

Erratum in

  • Cell. 2015 Oct 8;163(2):520-2.

Abstract

The 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.

Comment in

PMID:
25619691
PMCID:
PMC4422651
DOI:
10.1016/j.cell.2014.12.023
[Indexed for MEDLINE]
Free PMC Article

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