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Design of Sequence-Specific DNA Binding Molecules for DNA Methyltransferase Inhibition

Kang, JeenJoo S. and Meier, Jordan L. and Dervan, Peter B. (2014) Design of Sequence-Specific DNA Binding Molecules for DNA Methyltransferase Inhibition. Journal of the American Chemical Society, 136 (9). pp. 3687-3694. ISSN 0002-7863. PMCID PMC3985849. doi:10.1021/ja500211z.

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The CpG dyad, an important genomic feature in DNA methylation and transcriptional regulation, is an attractive target for small molecules. To assess the utility of minor groove binding oligomers for CpG recognition, we screened a small library of hairpin pyrrole-imidazole polyamides targeting the sequence 5′-CGCG-3′ and assessed their sequence specificity using an unbiased next-generation sequencing assay. Our findings indicate that hairpin polyamide of sequence PyImβIm-γ-PyImβIm (1), previously identified as a high affinity 5′-CGCG-3′ binder, favors 5′-GCGC-3′ in an unanticipated reverse binding orientation. Replacement of one β alanine with Py to afford PyImPyIm-γ-PyImβIm (3) restores the preference for 5′-CGCG-3′ binding in a forward orientation. The minor groove binding hairpin 3 inhibits DNA methyltransferase activity in the major groove at its target site more effectively than 1, providing a molecular basis for design of sequence-specific antagonists of CpG methylation.

Item Type:Article
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URLURL TypeDescription CentralArticle Information
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2014 American Chemical Society. ACS AuthorChoice. Received: January 10, 2014. Publication Date (Web): February 6, 2014. Sequencing was conducted at the Millard and Muriel Jacobs Genetics and Genomics Laboratory at the California Institute of Technology. Mass spectrometry analyses were performed in the Mass Spectrometry Laboratory of the Division of Chemistry and Chemical Engineering at the California Institute of Technology. Gels were scanned in the Center for the Chemistry of Cellular Signaling at the California Institute of Technology. National Institutes of Health (grant numbers GM51747 and GM27681); Tobacco-Related Disease Research Program (award number 20DT-0037 to J.S.K., dissertation research award); American Cancer Society (grant number PF-10-015-01-CDD to J.L.M., postdoctoral fellowship). Funding for open access charge: National Institutes of Health (grant number GM51747). The authors declare no competing financial interest.
Funding AgencyGrant Number
California Tobacco-Related Disease Research Program20DT-0037
American Cancer SocietyPF-10-015-01-CDD
Issue or Number:9
PubMed Central ID:PMC3985849
Record Number:CaltechAUTHORS:20140224-135418497
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Official Citation:Design of Sequence-Specific DNA Binding Molecules for DNA Methyltransferase Inhibition JeenJoo S. Kang, Jordan L. Meier, and Peter B. Dervan Journal of the American Chemical Society 2014 136 (9), 3687-3694
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:43950
Deposited By: Tony Diaz
Deposited On:05 Mar 2014 19:41
Last Modified:10 Nov 2021 16:45

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