Single residues within the YTHDF intrinsically disordered region control m 6 A-dependent mRNA decay

Ricci, Benedetta; Sommer, Danika; Narvaez, Daymieri; Zhang, Ruqi; Geri, Jacob; Zaccara, Sara

doi:10.64898/2026.09.18.752746

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Single residues within the YTHDF intrinsically disordered region control m 6 A-dependent mRNA decay

Ricci, Benedetta, Sommer, Danika, Narvaez, Daymieri, Zhang, Ruqi, Geri, Jacob, Zaccara, Sara·2026

DOI 10.64898/2026.09.18.752746

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Abstract

SUMMARY: 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 m 6 A 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 m 6 A-dependent mRNA decay and alter recruitment to cytoplasmic RNA granules, without affecting intrinsic m 6 A 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.

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Tau is an m 6 A-associated RNA binding protein that causes RNA dysregulation in disease
Dixon, G., Keys, A., Rothamel, K., McKetney, J., Jiang, Y. X., Gordon, L. A., Page, M. L., Liu, C., Hou, K., Flanagan, K., et al. (2026) · doi:10.64898/2026.10.26.762095

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Authors: Ricci, B., Sommer, D., Narvaez, D., Zhang, R., Geri, J., & Zaccara, S.
Publisher: openRxiv
Published: 2026-09-22
DOI: 10.64898/2026.09.18.752746
Cited by: 1
References: 7
Type: Preprint
Licence: www.biorxiv.org/about/FAQ#license (vor)

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The paper: Ricci, B., Sommer, D., Narvaez, D., Zhang, R., Geri, J., & Zaccara, S. (2026). Single residues within the YTHDF intrinsically disordered region control m 6 A-dependent mRNA decay. https://doi.org/10.64898/2026.09.18.752746

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Single residues within the YTHDF intrinsically disordered region control m 6 A-dependent mRNA decay

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