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Guiding the Design of Synthetic DNA-Binding Molecules with Massively Parallel Sequencing

Meier, Jordan L. and Yu, Abigail S. and Korf, Ian and Segal, David J. and Dervan, Peter B. (2012) Guiding the Design of Synthetic DNA-Binding Molecules with Massively Parallel Sequencing. Journal of the American Chemical Society, 134 (42). pp. 17814-17822. ISSN 0002-7863. PMCID PMC3483022. doi:10.1021/ja308888c.

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Genomic applications of DNA-binding molecules require an unbiased knowledge of their high affinity sites. We report the high-throughput analysis of pyrrole-imidazole polyamide DNA-binding specificity in a 10^(12)-member DNA sequence library using affinity purification coupled with massively parallel sequencing. We find that even within this broad context, the canonical pairing rules are remarkably predictive of polyamide DNA-binding specificity. However, this approach also allows identification of unanticipated high affinity DNA-binding sites in the reverse orientation for polyamides containing β/Im pairs. These insights allow the redesign of hairpin polyamides with different turn units capable of distinguishing 5′-WCGCGW-3′ from 5′-WGCGCW-3′. Overall, this study displays the power of high-throughput methods to aid the optimal targeting of sequence-specific minor groove binding molecules, an essential underpinning for biological and nanotechnological applications.

Item Type:Article
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URLURL TypeDescription DOIArticle CentralArticle Information
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2012 American Chemical Society. ACS AuthorChoice. Received: September 6, 2012. Published: September 26, 2012. This work is supported by the National Institutes of Health (GM27681). J.L.M. is supported by a postdoctoral grant from the American Cancer Society (PF-10-015-01-CDD). We thank Adam Urbach for the gift of a precursor to compound 8. We also thank Adam Urbach (Trinity University) and Sarah Lockwood (UC Davis) for helpful discussions. The authors declare no competing financial interest.
Funding AgencyGrant Number
American Cancer SocietyPF-10-015-01-CDD
Issue or Number:42
PubMed Central ID:PMC3483022
Record Number:CaltechAUTHORS:20130304-142528005
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Official Citation:Guiding the Design of Synthetic DNA-Binding Molecules with Massively Parallel Sequencing Jordan L. Meier, Abigail S. Yu, Ian Korf, David J. Segal, and Peter B. Dervan Journal of the American Chemical Society2012134 (42), 17814-17822
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:37278
Deposited By: Tony Diaz
Deposited On:04 Mar 2013 22:37
Last Modified:09 Nov 2021 23:27

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