DS0405 -

Mechanisms of the mitosis to meiosis transition in the fission yeast Schizosaccharomyces pombe – MechaMiMe

Submission summary

The cell-cycle transition from mitosis to meiosis is a key differentiation process essential for the transmission of the genetic information to the next generation. The profound modifications in gene expression profiles imply the existence of molecular mechanisms to establish and maintain cell-type specific programs. In the fission yeast Schizosaccharomyces pombe, initiation of meiosis occurs upon nutrient starvation and depends on signalling pathways that converge to the induction of a complex transcriptional cascade finalized by sexual differentiation. In addition to transcription activation, an additional mechanism exists that controls the onset of meiosis. During vegetative growth, a subset of meiotic genes is repressed at a post-transcriptional level: the YTH-family RNA-binding protein Mmi1 (meiotic mRNA interception factor 1) selectively targets meiosis-specific transcripts for degradation by the nuclear exosome, thereby preventing untimely entry into meiosis.
Upon nutritional starvation, Mmi1 is sequestered in an RNP complex, which allows translation of meiotic mRNAs and progression of the cell through meiosis. This inhibitory complex includes the key meiosis inducer, the RNA-binding protein Mei2, and the lncRNA meiRNA. Failure to assemble this structure blocks the entry into meiosis, highlighting its biological relevance for sexual differentiation. To prevent ectopic inhibition of Mmi1, mitotic cells exploit transcriptional and post-translational mechanisms to control Mei2 abundance and activity.
We have recently found that Mmi1 stably associates in vivo with the evolutionary conserved Ccr4-Not complex, which functions in deadenylation of mRNAs in the cytoplasm. This interaction is functionally relevant because integrity of the Ccr4-Not complex is required for meiotic mRNA degradation during vegetative growth. Surprisingly, we have shown that the RNA deadenylases of the complex are dispensable, while the E3 ubiquitin ligase subunit is essential for controlling the levels of meiotic transcripts. Biochemical and genetic analyses demonstrated that this function is mechanistically linked to the ubiquitination and proteasome-dependent degradation of the Mmi1 inhibitor Mei2. Our work unveiled a novel circuit involved in the regulation of meiosis whereby a protein controls the levels of its own inhibitor. This ensures the maintenance of Mmi1 in a functional state leading to the persistent repression of meiotic mRNAs in vegetative cells. Thus, Mmi1 has a dual role: in nuclear mRNA surveillance, by targeting meiotic transcripts for degradation by the exosome, and in protein degradation, by recruiting Ccr4-Not to its own inhibitor Mei2.
Despite these progresses, a full understanding of the regulation of the mitosis to meiosis transition in fission yeast is still elusive. The aim of this proposal is to address the mechanism of the mutual control of Mmi1 and Mei2 and their precise role in the regulation of meiotic differentiation. Notably, we seek i) to identify the molecular determinants of the Mmi1-Mei2 interaction at an unprecedented resolution, and ii) to decipher the molecular basis of the inactivation of Mmi1 by Mei2. The project will be conducted using a combination of molecular, biochemical and genome-wide approaches and we anticipate that our work will lead to important conceptual advances in the understanding of meiosis onset, paving the way for future studies in metazoans.

Project coordination

Mathieu Rougemaille (Institut de Biologie Intégrative de la Cellule)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

I2BC/CNRS Institut de Biologie Intégrative de la Cellule
IJM Institut Jacques Monod

Help of the ANR 252,720 euros
Beginning and duration of the scientific project: - 36 Months

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