Cellular context restricts a promiscuous m6A reader IDR to a single functional effector interface for mRNA decay

Authors

Chan, W. Y., Jin, E., Cross, H., Masino, L., Ibrahim, F., Albihlal, W. S., Berger, D., Boot, J., Michrowska, A., Mouilleron, S., Skehel, M., Kranc, K. R., van Werven, F. J.

Abstract

N6-methyladenosine (m6A) is a conserved mRNA modification that regulates transcript stability, yet how m6A readers engage effectors remains unknown. We show that during yeast meiosis, the YTH-domain protein Pho92 promotes the decay of m6A-modified transcripts through an uncharacterised, promiscuous intrinsically disordered region (IDR). In vitro, the Pho92 IDR makes multiple contacts with the Ccr4-NOT deadenylase complex and drives tethered reporter decay in the absence of any single subunit. Yet in meiosis, turnover of endogenous m6A-modified transcripts strictly depends on a single interface: direct binding of the Pho92 IDR to Caf40. A single hydrophobic residue substitution is sufficient to abolish Caf40 binding and halt transcript decay. Human YTHDF proteins can functionally substitute for Pho92, but require multiple hydrophobic patches within the IDR for decay activity. Thus, on endogenous m6A-modified transcripts during meiosis, the promiscuous Pho92 IDR is restricted to a single functional interface, revealing unappreciated specificity in m6A-directed mRNA decay.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 06 Aug 2026.

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