Silvia Santos

 

From clocks to dominoes: cell cycle control principles during developmental transitions

The decision to divide is a fundamental cellular response and the correct partitioning of chromosomes between two daughter cells requires a tight regulation of the cell cycle machinery. The evolutionarily conserved networks that control cell division adapt and remodel in a variety of biological contexts - during embryonic development, in response to stresses (e.g. infections and cancer) and while keeping homeostasis. A striking example of this versatility occurs during embryonic development during the transition from early embryonic to somatic divisions in the embryo.

Cell division is dependent on the activation and de-activation cycles of cyclin-dependent kinase complexes and the switching between DNA duplication and DNA segregation in all cells. The existence of these evolutionary conserved core regulators of both the embryonic and the somatic cell cycles suggests that the fundamental principles that regulate both cycles are similar. However, the embryonic and the somatic cell cycles are very different. Divisions in the embryo are clock-like, fast, short and synchronous with no checkpoints or gap phases. With time, during lineage specification, these divisions become longer and asynchronous. The resulting somatic like cycles have checkpoint control and long gap phases, and the initiation of events is dependent on completion of early events, just like a falling domino. The question, thus, arises on how do the same cell cycle regulators self-organize and adapt to drive different cell division cycles?

To address this question, the potential student will use multi-disciplinary approaches to understand how cell cycle remodelling happens during human embryonic stem cell differentiation. These studies will have profound implications for understanding both normal development, reprograming and de-differentiation and the transition to disease states, such as cancer, where cell cycle regulation takes a central stage.

1. Araujo, A. R., Gelens, L., Sheriff, R. S. M. and Santos, S. D. M. (2016)
Positive feedback keeps duration of mitosis temporally insulated from upstream cell-cycle events.
Molecular Cell 64: 362-375. PubMed abstract

2. Santos, S. D. M., Wollman, R., Meyer, T. and Ferrell, J. E., Jr. (2012)
Spatial positive feedback at the onset of mitosis.
Cell 149: 1500-1513. PubMed abstract

3. Santos, S. D. M. and Ferrell, J. E. (2008)
On the cell cycle and its switches.
Nature 454: 288-289. PubMed abstract