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#Cdc6

2 public questions tagged with this topic.

Cell Cycle Regulation

What is the function of Cdc6 and Cdt1 in DNA replication?

Pre-replication complex formation establishes replication competence before S phase, separating helicase loading from activation. Origin recognition complex ORC marks replication origins throughout cell cycle at AT-rich sequences. In late mitosis and early G1 when CDK activity minimal due to APC/C-Cdh1 mediated cyclin degradation, AAA+ ATPase Cdc6 binds ORC and recruits chaperone Cdt1 bound to single hexamer of MCM2-7 helicase. ATP hydrolysis by Cdc6 and ORC opens MCM ring, allowing encirclement of double-stranded DNA and formation of inactive double hexamer encircling DNA in head-to-head orientation, designated licensed origin. No DNA unwinding occurs. At G1/S transition, DDK kinase Dbf4-Cdc7 and CDK2 phosphorylate MCM and factors Sld2, Sld3, and Dpb11, recruiting Cdc45 and GINS to form active CMG helicase that unwinds DNA and recruits polymerases alpha, delta, and epsilon. Without Cdc6 and Cdt1, MCM loading fails and S phase cannot start, while their subsequent CDK-dependent degradation and nuclear exclusion prevent re-licensing in same cycle.

Ref: Bell & Labib, Genes & Dev 2016, Pre-RC Assembly. Alberts 7th ed., Chapter 5, Replication Licensing.

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Cell Cycle Regulation

How does Cdc6 regulate DNA replication?

Origins are prepared for replication during G1 through hierarchical assembly of pre-replicative complex. Origin recognition complex remains bound to DNA throughout cell cycle serving as landing pad. ATPase Cdc6 then associates in G1 in ATP-bound form undergoing conformational change that stabilizes interaction with ORC and creates composite binding site for helicase chaperone complex comprising Cdt1 and MCM2-7 double hexamer. ATP hydrolysis by Cdc6 and ORC loads MCM rings encircling double-stranded DNA in head-to-head orientation for bidirectional replication. This licensed origin remains inert until activated in S phase by DDK phosphorylation recruiting Cdc45 and CDK phosphorylation of Treslin and RecQL4 facilitating GINS association forming active CMG helicase Cdc45-MCM-GINS. After initiation, Cdc6 becomes phosphorylated by CDK2 at Ser/Thr-Pro motifs, translocates to cytoplasm and targeted for recognition by SCF-Cdc4 ligase for degradation, removing ability to load new MCMs. In yeast APC/C also contributes to clearance. Mutations impairing Cdc6 ATPase activity prevent MCM loading, causing severe replication defects, confirming its role as essential helicase loader linking G1 low CDK environment to replication competence.

Ref: Bell & Dutta, Origin Licensing by Cdc6 and MCM Loading, Annu Rev Biochem 2002; Alberts, Molecular Biology of the Cell, Chapter 5, DNA Replication Initiation.

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