Practice question

Commitment to S phase involves transcriptional and posttranslational steps driven by Cyclin E-CDK2 activity pulse. During early G1, Cyclin D-CDK4/6 initiates partial Rb phosphorylation after mitogen induction, allowing modest E2F-dependent synthesis of Cyclin E. Rising Cyclin E binds CDK2, fully activating kinase normally restrained by inhibitors p21 and p27. Cyclin E-CDK2 hyperphosphorylates Rb at additional sites, liberating large pool of E2F1-3 which amplify expression of Cyclin A, Cdc6, MCM helicase components, dihydrofolate reductase and Pol alpha. Concurrently Cyclin E-CDK2 phosphorylates p27 at Thr187 creating phosphodegron recognized by SCF-Skp2-Cks1, leading to degradation and reinforcement of CDK2 activity. It also phosphorylates NPAT regulator of histone genes, Cdc45 recruitment factors Treslin and RecQL4, directly promoting origin firing and replication complex assembly. Cyclin E levels then fall through autophosphorylation induced recognition by SCF-Fbw7 ligase, producing transient spike. Amplification of Cyclin E in cancers causes premature S entry, centrosome overduplication, replication stress and chromosome 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.