Article abstract
Nature Chemical Biology 1, 210 - 215 (2005)
Published online: 31 July 2005 | doi:10.1038/nchembio724
Inhibiting transcription of chromosomal DNA with antigene peptide nucleic acids
Bethany A Janowski1,2, Kunihiro Kaihatsu1,2, Kenneth E Huffman1,2, Jacob C Schwartz1,2, Rosalyn Ram1,2, Daniel Hardy2, Carole R Mendelson2 & David R Corey1,2
Abstract
Synthetic molecules that recognize specific sequences within cellular DNA are potentially powerful tools for investigating chromosome structure and function. Here, we designed antigene peptide nucleic acids (agPNAs) to target the transcriptional start sites for the human progesterone receptor B (hPR-B) and A (hPR-A) isoforms at sequences predicted to be single-stranded within the open complex of chromosomal DNA. We found that the agPNAs were potent inhibitors of transcription, showing for the first time that synthetic molecules can recognize transcription start sites inside cells. Breast cancer cells treated with agPNAs showed marked changes in morphology and an unexpected relationship between the strictly regulated levels of hPR-B and hPR-A. We confirmed these phenotypes using siRNAs and antisense PNAs, demonstrating the power of combining antigene and antisense strategies for gene silencing. agPNAs provide a general approach for controlling transcription initiation and a distinct option for target validation and therapeutic development.
- Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
- Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
Correspondence to: David R Corey1,2 e-mail: david.corey@utsouthwestern.edu
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