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Single residues within the YTHDF intrinsically disordered region control m 6 A-dependent mRNA decay
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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“Given that some m 6 A-reader proteins have roles in trafficking mRNA to stress granules to promote RNA decay 46 , it is plausible that tauRNA binding also affects this process, potentially providing a mechanism through which hnRNPA2B1 promotes mRNA decay through tau.”
From Tau is an m 6 A-associated RNA binding protein that causes RNA dysregulation in disease (2026) · cites this paper as [46]
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Nishimasu, H., Shi, X., Ishiguro, S., Gao, L., Hirano, S., Okazaki, S., Noda, T., Abudayyeh, O. O., Gootenberg, J. S., Mori, H., et al. (2018) · Science · doi:10.1126/science.aas9129 · Cited by 1,100
Microenvironment mapping via Dexter energy transfer on immune cells
Geri, J. B., Oakley, J. V., Reyes-Robles, T., Wang, T., McCarver, S. J., White, C. H., Rodriguez-Rivera, F. P., Parker, D. L., Hett, E. C., Fadeyi, O. O., et al. (2020) · Science · doi:10.1126/science.aay4106 · Cited by 481
Self-citationAbsolute quantification of single-base m6A methylation in the mammalian transcriptome using GLORI
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Massively parallel assessment of human variants with base editor screens
Hanna, R. E., Hegde, M., Fagre, C. R., DeWeirdt, P. C., Sangree, A. K., Szegletes, Z., Griffith, A., Feeley, M. N., Sanson, K. R., Baidi, Y., et al. (2021) · Cell · doi:10.1016/j.cell.2021.01.012 · Cited by 316
Massively parallel assessment of human variants with base editor screens
Hanna, R. E., Hegde, M., Fagre, C. R., DeWeirdt, P. C., Sangree, A. K., Szegletes, Z., Griffith, A., Feeley, M. N., Sanson, K. R., Baidi, Y., et al. (2020) · doi:10.1101/2020.05.17.100818 · Cited by 314
Context-dependent functional compensation between Ythdf m6A reader proteins
Lasman, L., Krupalnik, V., Viukov, S., Mor, N., Aguilera-Castrejon, A., Schneir, D., Bayerl, J., Mizrahi, O., Peles, S., Tawil, S., et al. (2020) · Genes & Development · doi:10.1101/gad.340695.120 · Cited by 243
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“However, neither site has been annotated as phosphorylated in available proteomic datasets 37 , largely because the surrounding IDR sequence lacks nearby tryptic cleavage sites, which may limit the detection of peptides in conventional trypsin-based phosphoproteomics 68 .”
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Cited by
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
Metadata
- Authors
- Ricci, B., Sommer, D., Narvaez, D., Zhang, R., Geri, J., & Zaccara, S.
- Publisher
- openRxiv
- Published
- 2026-09-22
- Cited by
- 1
- References
- 7
- Type
- Preprint
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