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#Cdt1

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

What is the role of Geminin in the cell cycle?

Eukaryotic replication origins must fire exactly once per cell cycle, a requirement enforced by strict licensing control. In G1, origin recognition complex recruits Cdc6 and Cdt1 to load MCM2-7 double hexamer helicases to form pre-replicative complexes. Upon S-phase entry, CDK and DDK activations fire origins and simultaneously trigger elimination of licensing factors to prevent re-assembly. Geminin provides a crucial additional layer independent of phosphorylation. Synthesized from S phase onward and stable through G2 and early mitosis, geminin directly binds coiled-coil domain of Cdt1 with high affinity, masking the MCM-interacting surface and blocking recruitment of additional MCM complexes to already replicated origins. Accumulation is cell cycle regulated: in late mitosis and G1, APC/C-Cdh1 polyubiquitinates geminin for proteasomal destruction, releasing Cdt1 for new licensing only when low CDK environment is appropriate. Depletion of geminin induces rereplication leading to double-strand breaks, checkpoint activation and apoptosis, while overexpression blocks S phase, demonstrating essential role as inhibitor of origin re-licensing ensuring once-per-cycle duplication. 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: McGarry & Kirschner, Geminin prevents DNA rereplication, Cell 1998; Alberts et al., Molecular Biology of the Cell, Chapter 5, Origin Licensing.

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