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

121 Citations (Scopus)

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 - Sep 2005
Externally publishedYes

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Peptide Nucleic Acids
DNA
Chromosome Structures
Transcription Initiation Site
Gene Silencing
Protein Isoforms
Breast Neoplasms
Phenotype
progesterone receptor B

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Janowski, B. A., Kaihatsu, K., Huffman, K. E., Schwartz, J. C., Ram, R., Hardy, D., ... Corey, D. R. (2005). Inhibiting transcription of chromosomal DNA with antigene peptide nucleic acids. Nature Chemical Biology, 1(4), 210-215. https://doi.org/10.1038/nchembio724

Inhibiting transcription of chromosomal DNA with antigene peptide nucleic acids. / Janowski, Bethany A.; Kaihatsu, Kunihiro; Huffman, Kenneth E.; Schwartz, Jacob C; Ram, Rosalyn; Hardy, Daniel; Mendelson, Carole R.; Corey, David R.

In: Nature Chemical Biology, Vol. 1, No. 4, 09.2005, p. 210-215.

Research output: Contribution to journalArticle

Janowski, BA, Kaihatsu, K, Huffman, KE, Schwartz, JC, Ram, R, Hardy, D, Mendelson, CR & Corey, DR 2005, 'Inhibiting transcription of chromosomal DNA with antigene peptide nucleic acids.', Nature Chemical Biology, vol. 1, no. 4, pp. 210-215. https://doi.org/10.1038/nchembio724
Janowski, Bethany A. ; Kaihatsu, Kunihiro ; Huffman, Kenneth E. ; Schwartz, Jacob C ; Ram, Rosalyn ; Hardy, Daniel ; Mendelson, Carole R. ; Corey, David R. / Inhibiting transcription of chromosomal DNA with antigene peptide nucleic acids. In: Nature Chemical Biology. 2005 ; Vol. 1, No. 4. pp. 210-215.
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