Cell cycle progression mechanisms: slower cyclin-D/CDK4 activation and faster cyclin-E/CDK2

Dysregulation of cyclin-dependent kinases (CDKs) impacts cell proliferation, driving cancer. Here, we ask why the cyclin-D/CDK4 complex governs cell cycle progression through the longer G1 phase, whereas cyclin-E/CDK2 regulates the short G1/S phase transition. We consider the experimentally established high-level bursting of cyclin-E, and sustained duration of elevated cyclin-D expression in the cell, available experimental cellular and structural data, and comprehensive explicit solvent molecular dynamics simulations to provide the mechanistic foundation of the distinct activation scenarios of cyclin-D/CDK4 and cyclin-E/CDK2 in the G1 phase and G1/S transition of the cell cycle, respectively. These lead us to propose slower activation of cyclin-D/CDK4 and rapid activation of cyclin-E/CDK2. Importantly, we determine the mechanisms through which this occurs, offering innovative CDK4 drug design considerations. Our insightful mechanistic work addresses the compelling cell cycle regulation question and illuminates the distinct activation speeds in the G1 versus G1/S phases, which are crucial for cell function. StatementOur work provides an unprecedented mechanistic understanding of the distinct activation scenarios of cyclin-D/CDK4 and cyclin-E/CDK2 in cell cycle regulation, underpinning the slower activation of cyclin-D/CDK4 in the more extended G1 phase and the rapid activation of cyclin-E/CDK2 in the brief G1/S transition. Our findings address a long-standing question in cell cycle biology and suggest the design of targeted CDK4 inhibitors.