G1/S transition also known as restriction point in mammals marks commitment to DNA replication independent of extracellular mitogens thereafter. Regulation centers on retinoblastoma protein phosphorylation cascade. Mitogens induce cyclin D-CDK4/6 via Ras-MAPK pathway which initiates partial phosphorylation of Rb family proteins pRb, p107, p130 at specific serine sites, displacing histone deacetylases and allowing transcription of cyclin E gene driven by E2F1-3. Cyclin E then associates with CDK2, activated by CAK phosphorylation, forming cyclin E-CDK2 holoenzyme that hyperphosphorylates Rb at additional sites including Thr373, Ser612, causing complete dissociation and full E2F-dependent transcription of S-phase genes encoding cyclin A, MCM2-7, PCNA, DNA polymerase alpha and delta, thymidine kinase, and dihydrofolate reductase. Cyclin E-CDK2 also phosphorylates p27Kip1 Thr187 creating phosphodegron for SCF-Skp2 ubiquitination establishing positive feedback loop making transition switch-like irreversible. Loss of cyclin E arrests cells in G1 despite mitogen presence, proving essential role in governing G1/S progression. This circuitry is highly conserved across eukaryotes, integrating growth factor signals, DNA damage surveillance, and developmental cues, and its disruption frequently underlies oncogenesis, providing targets for checkpoint inhibitors and cancer therapeutics.
Ref:
Dulic et al., Cell 1992, Cyclin E-CDK2 at G1/S. Alberts 7th ed., Chapter 17, Restriction Point Control.
