Broad specificity profiling of TALENs results in engineered nucleases with improved DNA-cleavage specificity View Full Text


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Article Info

DATE

2014-04

AUTHORS

John P Guilinger, Vikram Pattanayak, Deepak Reyon, Shengdar Q Tsai, Jeffry D Sander, J Keith Joung, David R Liu

ABSTRACT

Although transcription activator-like effector nucleases (TALENs) can be designed to cleave chosen DNA sequences, TALENs have activity against related off-target sequences. To better understand TALEN specificity, we profiled 30 unique TALENs with different target sites, array length and domain sequences for their abilities to cleave any of 10(12) potential off-target DNA sequences using in vitro selection and high-throughput sequencing. Computational analysis of the selection results predicted 76 off-target substrates in the human genome, 16 of which were accessible and modified by TALENs in human cells. The results suggest that (i) TALE repeats bind DNA relatively independently; (ii) longer TALENs are more tolerant of mismatches yet are more specific in a genomic context; and (iii) excessive DNA-binding energy can lead to reduced TALEN specificity in cells. Based on these findings, we engineered a TALEN variant that exhibits equal on-target cleavage activity but tenfold lower average off-target activity in human cells. More... »

PAGES

429-435

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nmeth.2845

    DOI

    http://dx.doi.org/10.1038/nmeth.2845

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1002278800

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/24531420


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