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Defining the sequence-recognition profile of DNA-binding molecules

Warren, Christopher L. and Kratochvil, Natasha C. S. and Hauschild, Karl E. and Foister, Shane and Brezinski, Mary L. and Dervan, Peter B. and Phillips, George N., Jr. and Ansari, Aseem Z. (2006) Defining the sequence-recognition profile of DNA-binding molecules. Proceedings of the National Academy of Sciences of the United States of America, 103 (4). pp. 867-872. ISSN 0027-8424. PMCID PMC1347994.

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[img] PDF (Fig. 6. Correlation plot of PA1. Intensity is plotted versus intensity for two of the four CSI microarray replicates. Intensities have been normalized and background has been subtracted so that the mean intensity is zero. Average correlation value ...) - Supplemental Material
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[img] PDF (Fig. 7. Histogram of intensities for PA1) - Supplemental Material
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[img] PDF (Fig. 8. Plot of flanking nucleotides for PA1 consensus sequence) - Supplemental Material
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[img] PDF (Fig. 9. Correlation and histogram plots of PA2 with Exd) - Supplemental Material
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[img] PDF (Fig. 10. CSI profile data for Exd.) - Supplemental Material
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Determining the sequence-recognition properties of DNA-binding proteins and small molecules remains a major challenge. To address this need, we have developed a high-throughput approach that provides a comprehensive profile of the binding properties of DNA-binding molecules. The approach is based on displaying every permutation of a duplex DNA sequence (up to 10 positional variants) on a microfabricated array. The entire sequence space is interrogated simultaneously, and the affinity of a DNA-binding molecule for every sequence is obtained in a rapid, unbiased, and unsupervised manner. Using this platform, we have determined the full molecular recognition profile of an engineered small molecule and a eukaryotic transcription factor. The approach also yielded unique insights into the altered sequence-recognition landscapes as a result of cooperative assembly of DNA-binding molecules in a ternary complex. Solution studies strongly corroborated the sequence preferences identified by the array analysis.

Item Type:Article
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URLURL TypeDescription CentralArticle Information
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2006 by The National Academy of Sciences of the USA Contributed by Peter B. Dervan, November 11, 2005. Published online before print January 17, 2006, 10.1073/pnas.0509843102 We thank D. Page and C. Kendziorski for helpful discussions and L. Vanderploeg for help with the figures. We gratefully acknowledge the support of the University of Wisconsin Industrial and Economic Development Research Program and the National Foundation–March of Dimes (A.Z.A.), Computation and Informatics in Biology and Medicine Training Grant T15LM007359 (to C.L.W.), and National Institutes of Health Grant GM51747 (to P.B.D.). Conflict of interest statement: No conflicts declared.
Funding AgencyGrant Number
University of WisconsinUNSPECIFIED
National Foundation - March of DimesUNSPECIFIED
NIH Predoctoral FellowshipT15LM007359
Subject Keywords:chemical genomics; ligand–DNA recognition
Issue or Number:4
PubMed Central ID:PMC1347994
Record Number:CaltechAUTHORS:WARpnas06
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Official Citation:Christopher L. Warren, Natasha C. S. Kratochvil, Karl E. Hauschild, Shane Foister, Mary L. Brezinski, Peter B. Dervan, George N. Phillips, Jr., and Aseem Z. Ansari Defining the sequence-recognition profile of DNA-binding molecules PNAS 2006 103 (4) 867-872; published ahead of print January 17, 2006, doi:10.1073/pnas.0509843102
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5988
Deposited By: Archive Administrator
Deposited On:10 Nov 2006
Last Modified:26 Nov 2019 11:15

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