Which Cyclin-CDK complex is responsible for the G1/S transition?
Transition from growth phase G1 into DNA synthesis S phase requires activation of gene expression program and licensing factor conversion. In early G1, Cyclin D-CDK4/6 partially phosphorylates Rb after mitogen stimulation allowing limited E2F activity producing Cyclin E. Cyclin E accumulation reaches zenith in late G1 forming active kinase with CDK2. Cyclin E-CDK2 completes hyperphosphorylation of Rb at distinct sites including Ser612 Ser807, fully dissociating Rb from E2F1-E2F3 activators. Liberated E2F-DP heterodimers bind promoters with TTTCCCGC motifs driving transcription of replication genes such as Cyclin A, dihydrofolate reductase, thymidylate synthase, PCNA, Cdc6, CDT1, MCM helicase subunits and DNA polymerase alpha delta epsilon. Simultaneously Cyclin E-CDK2 phosphorylates Kip1 inhibitor p27 at Thr187 creating phosphodegron for SCF-Skp2-Cks1 ubiquitination and degradation, eliminating CDK2 inhibition. It also phosphorylates Treslin TICRR and RecQL4 facilitating Cdc45-MCM-GINS helicase activation for origin firing. Expression transient because SCF-Fbw7 targets autophosphorylated Cyclin E for destruction, restricting activity window. Amplification frequently observed in ovarian and breast cancers driving replication stress and genomic instability. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.
Ref: Hinds, Cyclin E-CDK2 Complex and G1/S Transition Control, Cell Cycle 2002; Alberts et al., Chapter 17, G1/S Regulator.