Inhibiting Transcription of Chromosomal Dna With Antigene Peptide Nucleic Acids

Bethany A. Janowski, Kunihiro Kaihatsu, Kenneth E. Huffman, Jacob C. Schwartz, Rosalyn Ram, Daniel Hardy, Carole R. Mendelson, David R. Corey

Research output: Contribution to journalArticle

125 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)210-215
Number of pages6
JournalNature chemical biology
Volume1
Issue number4
DOIs
StatePublished - Jul 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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