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DNA aptamers against the DUX4 protein reveal novel therapeutic implications for FSHD
Author(s) -
Klingler Christian,
Ashley Jon,
Shi Ke,
Stiefvater Adeline,
Kyba Michael,
Sinnreich Michael,
Aihara Hideki,
Kinter Jochen
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902696
Subject(s) - aptamer , oligonucleotide , transcription factor , systematic evolution of ligands by exponential enrichment , förster resonance energy transfer , dna , computational biology , biology , cancer research , chemistry , microbiology and biotechnology , genetics , fluorescence , gene , rna , physics , quantum mechanics
Aberrant expression of the transcription factor double homeobox protein 4 (DUX4) can lead to a number of diseases including facio‐scapulo‐humeral muscular dystrophy (FSHD), acute lymphoblastic leukemia, and sarcomas. Inhibition of DUX4 may represent a therapeutic strategy for these diseases. By applying Systematic Evolution of Ligands by EXponential Enrichment (SELEX), we identified aptamers against DUX4 with specific secondary structural elements conveying high affinity to DUX4 as assessed by fluorescence resonance energy transfer and fluorescence polarization techniques. Sequences analysis of these aptamers revealed the presence of two consensus DUX4 motifs in a reverse complementary fashion forming hairpins interspersed with bulge loops at distinct positions that enlarged the binding surface with the DUX4 protein, as determined by crystal structure analysis. We demonstrate that insertion of specific structural elements into transcription factor binding oligonucleotides can enhance specificity and affinity.