UPS and Kinases—Gatekeepers of the G1/S Transition

The G1/S transition is a highly regulated and pivotal checkpoint in the cell cycle, where the cell decides whether to commit to DNA replication and subsequent division or enter a non-dividing state. This checkpoint serves as a critical control point for preventing uncontrolled cell proliferation and maintaining genomic stability. The major driving force underlying the G1/S transition is the sequential activation of Cyclin-dependent kinases (CDKs), which is regulated by the coordinated binding of Cyclin partners, as well as the phosphorylation and ubiquitin-mediated degradation of both Cyclin partners and Cyclin-dependent kinase inhibitors (CKIs). Various E3 ligase families govern the timely degradation of these regulatory proteins, with their activity intricately controlled by phosphorylation events. This coordination enables the cells to efficiently translate the environmental cues and molecular signaling inputs to determine their fate. We explore the evolution of three distinct models describing the G1/S transition, highlighting how the traditional linear model is being challenged by recent paradigm shifts and conflicting findings. These advances reveal emerging complexity and unresolved questions in the field, particularly regarding how the latest insights into coordinated phosphorylation and ubiquitination-dependent degradation integrate into contemporary models of the G1/S transition.