Mammalian cells integrate growth factor signals and stress signals in order to make the decision to enter the cell cycle during G1 phase. Cell cycle entry is regulated by activation of the transcription factor E2F, Cyclin Dependent Kinase 2 (CDK2), and inactivation of the E3 ubiquitin ligase APC/C. We recently showed that once APC/C inactivates, cells are fully committed to the cell cycle, and that APC/C inactivation is mediated by a dual negative feedback loop between APC/C and Early Mitotic Inhibitor 1 (Emi1). We are currently investigating how stress signaling pathways during G1 phase regulate this feedback loop to prevent cell cycle entry and promote quiescence and repair and how this mechanism is perturbed in cancer cells. There is considerable single-cell variability in the response to stress when cells are in G1 phase. Some cells can respond to DNA damage by exiting to quiescence while other cells will continue to enter S phase with damaged DNA. We are investigating how cells make these opposite fate decisions and what are the consequences of choosing one fate over the other.
|Cappell, Steven D; Mark, Kevin G; Garbett, Damien et al. (2018) EMI1 switches from being a substrate to an inhibitor of APC/CCDH1 to start the cell cycle. Nature 558:313-317|