#G1/S transition

Cell Division

Which of the following proteins is responsible for regulating the G1/S transition?

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

Ref: Dulic et al., Cell 1992, Cyclin E-CDK2 at G1/S. Alberts 7th ed., Chapter 17, Restriction Point Control.

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Cell Cycle Regulation

In yeast, which protein is the functional equivalent of Rb in regulating the G1/S transition?

In mammalian cells, Rb represses E2F until cyclin D-CDK4/6 phosphorylates pocket domain, but budding yeast Saccharomyces cerevisiae lacks Rb ortholog and uses functionally analogous repressor Whi5 to regulate Start checkpoint analogous to Restriction Point. Whi5 contains CDK phosphorylation sites and binds heterodimeric transcription factor SBF composed of Swi4 DNA-binding protein recognizing SCB elements and Swi6 coactivator. In early G1 when CDK activity low, unphosphorylated Whi5 resides in nucleus, physically interacting with SBF at promoters of CLN1, CLN2, CLB5, and many cell wall synthes

Ref: Cross et al., Annu Rev Cell Dev Biol 2007, Yeast G1/S Control. NCBI Bookshelf: Whi5 Rb Analog.

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Cell Cycle Regulation

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 g

Ref: Hinds, Cyclin E-CDK2 Complex and G1/S Transition Control, Cell Cycle 2002; Alberts et al., Chapter 17, G1/S Regulator.

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Cell Cycle Regulation

The G1/S transition is tightly regulated by:

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 phosphorylate

Ref: Hinds & Weinberg, Cell Cycle Control by Cyclin E-CDK2, Curr Opin Cell Biol; Alberts et al., Chapter 17, G1/S Transition.

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