DNA Aptamers Against the DUX4 Protein Reveal Novel Therapeutic Implications for FSHD

Overview

Journal FASEB J

Specialties Biology
Physiology

Date 2020 Feb 6

PMID 32020675

Citations 15

Authors

Christian Klingler

Jon Ashley

Ke Shi

Adeline Stiefvater

Michael Kyba

Michael Sinnreich

Hideki Aihara

Jochen Kinter

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Oligonucleotide Therapies for Facioscapulohumeral Muscular Dystrophy: Current Preclinical Landscape.

Beck S, Yokota T Int J Mol Sci. 2024; 25(16).

PMID: 39201751 PMC: 11354670. DOI: 10.3390/ijms25169065.

Structural Insights into Protein-Aptamer Recognitions Emerged from Experimental and Computational Studies.

Troisi R, Balasco N, Autiero I, Vitagliano L, Sica F Int J Mol Sci. 2023; 24(22).

PMID: 38003510 PMC: 10671752. DOI: 10.3390/ijms242216318.

Influence of Expression in Facioscapulohumeral Muscular Dystrophy and Possible Treatments.

Duranti E, Villa C Int J Mol Sci. 2023; 24(11).

PMID: 37298453 PMC: 10253551. DOI: 10.3390/ijms24119503.

An in silico FSHD muscle fiber for modeling DUX4 dynamics and predicting the impact of therapy.

Cowley M, Pruller J, Ganassi M, Zammit P, Banerji C Elife. 2023; 12.

PMID: 37184373 PMC: 10287159. DOI: 10.7554/eLife.88345.

Facioscapulohumeral muscular dystrophy: the road to targeted therapies.

Tihaya M, Mul K, Balog J, de Greef J, Tapscott S, Tawil R Nat Rev Neurol. 2023; 19(2):91-108.

PMID: 36627512 PMC: 11578282. DOI: 10.1038/s41582-022-00762-2.

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