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Translational control of the cdc25 cell cycle phosphatase: a molecular mechanism coupling mitosis to cell growth
1Unidad de Genética, Facultad de Ciencias, Universidad de Málaga, Campus Universitario de Teatinos, Spain.
Abstract:
The eukaryotic translation initiation factor 4A (eIF4A) is an RNA helicase required for translation initiation of eukaryotic mRNAs. By engineering fission yeast mutants with diminished eIF4A activity, we have found that translation of cdc25 mRNAs (a dosage-dependent activator of mitosis in all eukaryotic cells) is particularly sensitive to limitations of protein synthesis mediated by limited eIF4A activity. Genetic and biochemical analysis indicated that a rate-limited translation initiation of cdc25 mRNAs, exerted throughout its unusual 5' untranslated leader, acts as a molecular sensor to ensure that a minimum cell mass (protein synthesis) is attained before mitosis occurs. The Cdc13 cyclin B is also among the limited pool of proteins whose translation is sensitive to reduced translation initiation activity. Interestingly, the 5' leader sequences of cdc25 and cdc13 mRNAs have conserved features which are unusual in other yeast mRNAs, suggesting that common mechanisms operate in the expression of these two key mitotic activators at the translational level.
Insights
Limited eukaryotic translation initiation factor 4A (eIF4A) activity specifically impacts cdc25 mRNA translation. This ensures cells reach adequate size before mitosis, regulating cell cycle progression.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Eukaryotic translation initiation factor 4A (eIF4A) is an essential RNA helicase.
- eIF4A plays a critical role in initiating the translation of eukaryotic messenger RNAs (mRNAs).
- Dysregulation of translation can impact crucial cellular processes like cell division.
Purpose of the Study:
- To investigate the specific role of eIF4A activity in regulating the translation of key cell cycle genes.
- To understand how limitations in protein synthesis affect mitotic progression.
- To identify conserved translational control mechanisms for mitotic activators.
Main Methods:
- Engineering fission yeast mutants with reduced eIF4A activity.
- Genetic analysis to assess the impact on mRNA translation.
- Biochemical assays to study protein synthesis rates.
Main Results:
- Translation of cdc25 mRNAs is particularly sensitive to diminished eIF4A activity.
- A rate-limited translation initiation of cdc25 mRNA, via its 5' untranslated leader, acts as a cell size sensor.
- Translation of Cdc13 cyclin B is also sensitive to reduced eIF4A activity.
- Conserved, unusual 5' leader sequences in cdc25 and cdc13 mRNAs suggest shared translational regulation.
Conclusions:
- eIF4A-mediated translation control of cdc25 mRNA ensures proper cell mass attainment before mitosis.
- The 5' untranslated regions of cdc25 and cdc13 mRNAs harbor regulatory elements for translational control.
- Common translational mechanisms regulate the expression of key mitotic activators, ensuring cell cycle fidelity.