Genomic Effects of Polyamide/DNA Interactions on mRNA Expression

• Published in: Chemistry & biology Vol. 9; no. 7; pp. 821 - 827
• Main Authors: Supekova, Lubica, Pezacki, John Paul, Su, Andrew I., Loweth, Colin J., Riedl, Rainer, Geierstanger, Bernhard, Schultz, Peter G., Wemmer, David E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.07.2002
• Subjects: Binding Sites; Calreticulin - genetics; Colonic Neoplasms; Databases, Genetic; DNA - metabolism; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; Down-Regulation - genetics; Down-Regulation - physiology; Electrophoretic Mobility Shift Assay; Genes, bcl-1 - genetics; Humans; Lymphoid Enhancer-Binding Factor 1; Microscopy, Fluorescence; Nucleic Acid Conformation; Nylons - chemistry; Nylons - metabolism; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; RNA, Messenger - biosynthesis; Transcription Factors - analysis; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - physiology; Tumor Cells, Cultured
• ISSN: 1074-5521; 1879-1301
• DOI: 10.1016/S1074-5521(02)00174-6

Here we characterize the biological activity of a hairpin polyamide 1 that inhibits binding of the minor-groove transcription factor LEF-1, constitutively expressed in colon cancers. Genome-wide analysis of mRNA expression in DLD1 colon cancer cells treated with 1 reveals that a limited number of genes are affected; the most significant changes correspond to genes related to cell cycle, signaling, and proteolysis rather than the anticipated WNT signaling pathway. Treated cells display increased doubling time and hypersensitivity to DNA damage that most likely results from downregulation of DNA-damage checkpoint genes, including YWAE (14-3-3ϵ protein) and DDIT3. Promoter analyses on a genomic level revealed numerous potential polyamide binding sites and multiple possible mechanisms for transcriptional antagonism, underscoring the utility of gene expression profiling in understanding the effects of polyamides on transcription at the cellular level.