#CDK

Cell Cycle Regulation

Which kinase is involved in regulating the initiation of DNA replication in S phase?

Initiation of DNA replication at licensed origins depends on two kinase families that separate licensing from firing. DDK kinase complex Dbf4-Cdc7 phosphorylates MCM2-7 helicase at N-terminal serine-threonine clusters, promoting Cdc45 recruitment. Second trigger is S-phase CDK activity supplied by cyclin E-CDK2 that peaks at G1/S border and cyclin A-CDK2 that sustains activity into S phase. Cyclin E-CDK2 phosphorylates Treslin/TICRR at threonine 969, MTBP, RecQL4, and orthologs of yeast Sld2 and Sld3, enabling their binding to BRCT repeats of TopBP1 and assembly of Cdc45-MCM-GINS active helica

Ref: Labib, Genes & Dev 2010, Origin Activation. Limas & Cook, Genes & Dev 2019, CDK Roles S Phase.

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Cell Cycle Regulation

What is the role of Cyclins in the cell cycle?

Cyclins earned name due to fluctuating concentrations through cell cycle while CDKs remain relatively constant. Function is to activate CDKs by allosteric remodeling and to direct substrate choice through additional binding motifs. In G1, Cyclin D with CDK4/6 senses mitogens, Cyclin E with CDK2 triggers S-phase entry, Cyclin A with CDK2 drives S-phase progression and later with CDK1 primes mitosis, Cyclin B with CDK1 executes mitosis. Each cyclin contains conserved cyclin box domain and hydrophobic patch recognizing RXL motifs on substrates, plus localization signals determining nuclear or cen

Ref: Murray, Cyclins: Roles in Cell Cycle and Evolution, Cell; Alberts et al., Molecular Biology of the Cell, Chapter 17, Cyclin-CDK Functions.

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Cell Cycle Regulation

Which kinase initiates DNA replication by phosphorylating helicase activators?

Authentic initiation of DNA synthesis requires coordinated activation of MCM2-7 helicase loaded at licensed origins. Two S-phase kinases perform this: Cdc7-Dbf4 complex called DDK phosphorylates N-terminal tails of MCM2, MCM4 and MCM6 promoting Cdc45 recruitment, while CDK2-Cyclin E and CDK2-Cyclin A phosphorylate Treslin, Ticrr, RecQL4 and TopBP1 creating phospho-binding sites for assembling replication machinery including Cdc45-MCM-GINS active helicase and Pol epsilon recruitment. Entry dataset incorrectly lists p53 as initiating kinase; biologically p53 acts opposite as genome guardian. Upo

Ref: Labib, Mechanism of DNA Replication Initiation by DDK and CDK, Science 2010; NCBI Bookshelf, Regulation of Origin Firing by CDK2.

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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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