Gadgil, P. | bioRxiv Science

bioRxiv2025

A minimal model for the role of Rim4 in regulating meiotic exit in budding yeast

Meiosis ensures formation of haploid gametes through two rounds of chromosome segregation after one round of DNA replication. How this complex cell cycle process is restricted to two and only two divisions is poorly understood. In budding yeast, RNA-binding protein Rim4 binds various mRNAs to prevent their translation. At the onset of meiosis II, phosphorylation and degradation of Rim4, along with the concomitant release of sequestered mRNA, has an important role in ensuring meiotic exit. Building on previous work, we developed a parsimonious mathematical model of meiotic termination that elucidates the role of Rim4-mRNA release and translation of AMA1 mRNA in the fidelity of meiotic exit. Central to our model is the accumulation of Ama1 protein, a meiosis-specific activator of APC/C. Our mathematical model predicted further outcomes, which we tested experimentally. We found that either slowing Rim4 degradation or disrupting APC/CAma1 activity delayed meiosis II. In some cells, this disruption prevented meiotic exit entirely, leading them to re-enter cell cycle oscillations after meiosis II. These findings demonstrate that the timely activation of this regulatory network is crucial for ensuring irreversible meiotic exit.

cell biology↗

bioRxiv2024

Aneuploidy of Specific Chromosomes is Beneficial to Cells Lacking Spindle Checkpoint Protein Bub3

Aneuploidy typically poses challenges for cell survival and growth. However, recent studies have identified exceptions where aneuploidy is beneficial for cells with mutations in certain regulatory genes. Our research reveals that cells lacking the spindle checkpoint gene BUB3 exhibit aneuploidy of select chromosomes. While the spindle checkpoint is not essential in budding yeast, the loss of BUB3 and BUB1 increases the probability of chromosome missegregation compared to wildtype cells. Contrary to the prevailing assumption that the aneuploid cells would be outcompeted due to growth defects, our findings demonstrate that bub3{Delta} cells consistently maintained aneuploidy of specific chromosomes over many generations. We investigated whether the persistence of these additional chromosomes in bub3{Delta} cells resulted from the beneficial elevated expression of certain genes, or mere tolerance. We identified several genes involved in chromosome segregation and cell cycle regulation that confer an advantage to Bub3-depleted cells. Overall, our results suggest that the upregulation of specific genes through aneuploidy may provide a survival and growth advantage to strains with poor chromosome segregation fidelity. AUTHOR SUMMARYAccurate chromosome segregation is crucial for the proper development of all living organisms. Errors in chromosome segregation can lead to aneuploidy, characterized by an abnormal number of chromosomes, which generally impairs cell survival and growth. However, under certain stress conditions, such as in various cancers, cells with specific mutations and extra copies of advantageous chromosomes exhibit improved survival and proliferation. In our study, we discovered that cells lacking the spindle checkpoint protein Bub3 became aneuploid, retaining specific chromosomes. This finding was unexpected because although bub3{Delta} cells have a higher rate of chromosome mis-segregation, they were not thought to maintain an aneuploid karyotype. We investigated whether the increased copy number of specific genes on these acquired chromosomes offered a benefit to Bub3-deficient cells. Our results revealed that several genes involved in chromosome segregation and cell cycle regulation prevented the gain of chromosomes upon Bub3-depletion, suggesting that these genes confer a survival advantage. Overall, our study demonstrates that cells lacking Bub3 selectively retain specific chromosomes to increase the copy number of genes that promote proper chromosome segregation.

cell biology↗