A FISTFUL OF MOLECULES: CELLS ESCAPE AN OPERATIONAL MITOTIC CHECKPOINT THROUGH A STOCHASTIC PROCESS

The cell cycle culminates with the segregation of sister chromatids, which is a fundamental step in ensuring the transmission of unaltered genetic material. Chromosome segregation is carried out by the mitotic spindle, which captures and pulls sister chromatids towards the opposite poles. Anaphase starts when the correct bipolar attachment is achieved. Chromosomes migrate evenly to the two daughter cells, both inheriting the same genetic material. The presence of unattached kinetochore at anaphase onset is dangerous, since it may lead to unbalanced ploidy of daughter cells, with severe consequences for their survival. For this reason, improperly attached chromosomes activate the mitotic checkpoint that arrests cell division before anaphase. Cells can maintain an arrest for several hours but eventually will resume proliferation, a process we refer to as adaptation. Whether adapting cells bypass an active block or whether the block has to be removed to resume proliferation is not clear. Likewise, it is not known whether all cells of a genetically homogeneous population are equally capable to adapt. Here, we show that the mitotic checkpoint is operational when yeast cells adapt and that each cell has the same propensity to adapt. Our results are consistent with a model of the mitotic checkpoint where adaptation is driven by random fluctuations of APC/CCdc20 , the molecular species inhibited by the checkpoint. Our data provide a quantitative framework for understanding how cells overcome a constant stimulus that halts cell cycle progression.