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STARTlight: cell cycle START decision unraveled by single-cell microscopy, modeling and optogenetics

Periodic Reporting for period 1 - STARTlight (STARTlight: cell cycle START decision unraveled by single-cell microscopy, modeling and optogenetics)

Reporting period: 2018-04-01 to 2020-03-31

Cells across all kingdoms of life need to maintain tight control on their division process, which they use to replicate themselves. In particular, the decision of cells to initiate a round of division is a ubiquitous and essential process, whose dysregulation can dramatically affect cell viability in simple unicellular organisms, while contributing to carcinogenesis in organisms such as humans. The central goal of this proposal was to determine the key molecular mechanisms behind this decision process. To achieve this, we used a combination of cutting-edge experimental methods with data analysis and mathematical modeling to understand how and when individual budding yeast cells decide to divide. Our results have generated new fundamental knowledge on the regulation of the yeast cell division cycle which, thanks to the high degree of evolutionary conservation of cell division mechanisms among different organisms, may also be applicable to organisms such as humans.
Our work focused on budding yeast (also known as baker’s yeast), a well-studied and commonly used model organism. Using microscopy and cultivation techniques which enabled us to follow single yeast cells growing under the microscope, we obtained a wealth of new information on the dynamics of cell growth and key proteins that regulate the decision of yeast cells to divide (a process known as START). Our experimental observations were used to build and calibrate a mathematical model of START. This model was tested extensively by comparing its predictions with observed single-cell behaviors under normal and perturbed growth conditions. With our model, we were thus able to elucidate the sequence of molecular events leading up to the decision of cells to enter a new division cycle.
With our combination of experimental techniques and data analysis procedures, we were able to observe for the first time the dynamics of key START regulators, which had so far remained elusive. This new knowledge enabled us to considerably improve the mathematical modeling of START, which had so far been hampered by the lack of accurate single-cell dynamic data. Our results will be of great interest to biologists studying the regulation of cell division and the development of cancer in human cells.
Mathematical modeling of START incorporating experimental information on key regulator proteins