Single residues within the YTHDF intrinsically disordered region control m6A-dependent mRNA decay

Authors

Ricci, B., Sommer, D., Narvaez, D. A., Zhang, R., Geri, J. B., Zaccara, S.

Abstract

Intrinsically disordered regions (IDRs) mediate protein interactions, condensate partitioning, and regulatory control in RNA-binding proteins, yet the residue-level logic underlying IDR function has remained difficult to define using conventional fragment- and truncation-based approaches. Here, we apply cytosine and adenine base-editor screens to map residue-level regulation within the intrinsically disordered region of YTHDF2, a cytoplasmic reader that couples m6A to mRNA decay. By tiling base edits across YTHDF2 in a YTHDF1/YTHDF3-null background, we identify IDR residues that regulate YTHDF2-dependent cellular fitness. Interestingly, we identified residues that limit YTHDF2 decay activity. Their mutation disrupts endogenous protein-protein interactions and generates hyperactive YTHDF2 variants that promote m6A-dependent mRNA decay and alter recruitment to cytoplasmic RNA granules, without affecting intrinsic m6A binding or protein stability. These findings define the residue-level regulatory logic of the YTHDF2 IDR and establish base-editor screening as a strategy to uncover functional mechanisms encoded within IDR regions.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 23 Sep 2026.

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