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Cellular context restricts IDR plasticity to a single essential effector interface for m6A-dependent mRNA turnover [Chan_RNA-seq_experiment 3]

ABSTRACT: N6-methyladenosine (m6A) is a conserved mRNA modification that regulates transcript stability, yet how m6A reader proteins engage effectors remains poorly understood. Using yeast meiosis as a model, we investigated how the YTH-domain protein Pho92 promotes decay of m6A-modified transcripts through its 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, the cellular context of meiosis dictates which IDR-mediated contacts are functional for m6A turnover, adding a layer of specificity in post-transcriptional gene regulation.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE339410 | GEO | 2026/07/29

REPOSITORIES: GEO

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Cellular context restricts IDR plasticity to a single essential effector interface for m6A-dependent mRNA turnover [Chan_RNA-seq_experiment 2]

Project description:N6-methyladenosine (m6A) is a conserved mRNA modification that regulates transcript stability, yet how m6A reader proteins engage effectors remains poorly understood. Using yeast meiosis as a model, we investigated how the YTH-domain protein Pho92 promotes decay of m6A-modified transcripts through its 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, the cellular context of meiosis dictates which IDR-mediated contacts are functional for m6A turnover, adding a layer of specificity in post-transcriptional gene regulation.

2026-07-29 | GSE339409 | GEO

Cellular context restricts IDR plasticity to a single essential effector interface for m6A-dependent mRNA turnover [Chan_RNA-seq_experiment 1]

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m6A reader Pho92 is recruited co-transcriptionally and couples translation efficacy to mRNA decay to promote meiotic fitness in yeast [iCLIP_miCLIP-seq]

Project description:During meiosis, in Saccharomyces cerevisiae, N6-methyladenosine (m6A) modified transcripts are induced, of which the function is unknown. Here, we uncover the role of the m6A reader Pho92. Cross-linking immunoprecipitation (CLIP) revealed that Pho92 associates with meiotic mRNAs in both m6A dependent and independent manner. Incidentally, Pho92 resides in the nucleus during early meiosis and associates with nascent RNAs, which is mediated through its interaction with Paf1C. Transcripts bound by Pho92 show elevated translational efficiency while cells lacking Pho92 display a small, but notable, increase in mRNA levels but not in protein levels, suggesting role of Pho92 in translation and decay. We show that Pho92 associates with ribosomes where it promotes the decay of m6A modified transcripts, contingent on active translation and the CCR4-NOT complex. We propose that m6A reader Pho92 is loaded co-transcriptionally to promote translation and subsequent decay fate of m6A modified transcripts, which ensures gamete fitness.

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m6A reader Pho92 is recruited co-transcriptionally and couples translation efficacy to mRNA decay to promote meiotic fitness in yeast [pho92D_ime4D]

Project description:N6-methyladenosine (m6A) RNA modification impacts mRNA fate primarily via reader proteins, which dictate processes in development, stress, and disease. Yet little is known about m6A function in Saccharomyces cerevisiae, which occurs solely during early meiosis. Here we perform a multifaceted analysis of the m6A reader protein Pho92/Mrb1. Cross-linking immunoprecipitation analysis reveals that Pho92 associates with the 3’end of meiotic mRNAs in both an m6A-dependent and independent manner. Within cells, Pho92 transitions from the nucleus to the cytoplasm, and associates with translating ribosomes. In the nucleus Pho92 associates with target loci through its interaction with transcriptional elongator Paf1C. Functionally, we show that Pho92 promotes and links protein synthesis to mRNA decay. As such, the Pho92-mediated m6A-mRNA decay is contingent on active translation and the CCR4-NOT complex. We propose that the m6A reader Pho92 is loaded co-transcriptionally to facilitate correct translation and subsequent decay of m6A modified transcripts, and thereby promotes meiosis.

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m6A reader Pho92 is recruited co-transcriptionally and couples translation efficacy to mRNA decay to promote meiotic fitness in yeast [ime1D_ndt80D]

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m6A reader Pho92 is recruited co-transcriptionally and couples translation efficacy to mRNA decay to promote meiotic fitness in yeast [Polysome]

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Yeast m6A methylated mRNAs are enriched on translating ribosomes during meiosis, and under Rapamycin treatment

Project description:Interest in mRNA methylation has exploded in recent years. The sudden interest in a 40 year old discovery was due in part to the recent finding of FTO?s (Fat Mass Obesity) N6-methyl-adenosine (m6A) deaminase activity, thus suggested a link between obesity-associated diseases and the presence of m6A in mRNA. Another catalyst of the sudden rise in mRNA methylation research was the release of mRNA methylomes for human, mouse and Saccharomyces cerevisiae. However, the molecular function, or functions of this mRNA ?epimark? remain to be discovered. There is supportive evidence that m6A could be a mark for mRNA degradation due to its binding to YTH domain proteins, and consequently being chaperoned to P bodies. Nonetheless, only a subpopulation of the methylome was found binding to YTHDF2 in HeLa cells. The model organism Saccharomyces cerevisiae, has only one YTH domain protein (Pho92, Mrb1), which targets PHO4 transcripts for degradation under phosphate starvation. However, mRNA methylation is only found under meiosis inducing conditions, and PHO4 transcripts are apparently non-methylated. In this paper we set out to investigate if m6A could function alternatively to being a degradation mark in S. cerevisiae, we also sought to test whether it can be induced under non-standard sporulation conditions. We find associations between the presence of m6A and message translatability. We also find m6A induction following prolonged rapamycin treatment. GeneChip analyses were performed to investigate the distribution of early meiotic transcripts (3hours) on different polysome and monosome fractions

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m6A is decoded by modified tRNAs to coordinate mRNA decay [RNA-Seq]

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