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Motif-Selective DNA Recognition and Promoter-Dependent Transcriptional Repression by a Cyclic Pyrrole/Lysine
Mitsuharu Ooga1, Hokun Yum2, Yuki Hirose1
1Department of Chemistry, Graduate School of Science Kyoto University, Kyoto, Japan.
Abstract:
Sequence-selective control of gene expression by synthetic DNA-binding molecules is attractive for developing chemical biology tools and potential therapeutic applications. Here we report a cyclic pyrrole/lysine polyamide (cPKP) that preferentially binds AT-rich DNA, with selective recognition of ATAT and ATGT motifs. In a HeLa nuclear extract-based transcription system, cPKP repressed transcription in a promoter-dependent manner, showing stronger inhibition of a cytomegalovirus (CMV) core promoter than of the human c-MYC promoter. RNA sequencing showed that cPKP was associated with downregulation of genes whose proximal promoters were enriched for ATAT and ATGT motifs, while causing limited perturbation of global cellular homeostasis in HeLa cells. Together, these results establish cPKP as a motif-selective DNA-binding scaffold that can modulate transcription in a promoter-dependent manner with limited global transcriptomic perturbation in human cells.
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