Journal Article

PUBDB-2026-01391

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A DNA‐Based Binding Assay for the m 6 A‐RNA Reader Proteins

Bedi, R. K.Extern*EMBL* ; Caflisch, A. (Corresponding author)Extern*EMBL*

2026
Wiley-VCH Weinheim

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Please use a persistent id in citations: doi:10.1002/cbic.202500897  doi:10.3204/PUBDB-2026-01391

Abstract: N6-methyladenosine (m6A) is the most prevalent internal modification in eukaryotic messenger RNA. Dysregulation of m6A-RNA signaling has been implicated in a wide range of human diseases. The N6-methyladenosine modifications in DNA (6mA) is much rarer, and its role is still debated. Here, we report the first holo crystal structure of the m6A-RNA reader YTHDC2. The 1.6 Å resolution structure of YTHDC2 bound to the single-strand (ss) hexanucleotide GG(6mA)CTA-DNA shows an essentially identical binding mode of (6mA)CT-DNA as (m6A)CU-RNA in the other four human reader proteins YTHDC1 and YTHDF1-3. Comparative analysis of the binding of fluorescent-labeled 6mA-ssDNA and m6A-RNA revealed that the five human m6A-RNA readers exhibit slightly stronger binding affinity for 6mA-modified DNA with a factor ranging from about 1.3 for YTHDC1 to 30 for YTHDC2. Given the similar affinity and the similar binding mode of 6mA-ssDNA and m6A-RNA, we set up to develop a fluorescence polarization (FP) binding assay that uses a fluorescent-labeled 6mA-containing ssDNA as probe. The DNA-based FP assay shows high stability and robustness, making it suitable for high-throughput screening applications. The assay provides a powerful and cost-efficient platform to accelerate the discovery of small-molecule modulators targeting m6A-RNA reader proteins.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)

Appears in the scientific report 2026

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Database coverage:
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