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#replication control

3 public questions tagged with this topic.

Cell Cycle Regulation

In the regulation of DNA replication, which factor ensures that origins fire only once per cycle?

Eukaryotes must replicate each DNA segment exactly once per cell cycle to avoid re-replication which causes double-strand breaks and genomic instability. Origin licensing is restricted to G1 when CDK activity low: ORC, Cdc6, and Cdt1 load double hexamer of MCM2-7 helicase. At S onset, CDK and DDK activate helicase, but re-loading must be blocked. Geminin protein accumulating from S through early mitosis directly binds Cdt1 through extended coiled-coil domain, sterically occluding MCM-interacting surface and preventing second helicase loading. Concurrently, cyclin A-CDK2 phosphorylates Cdt1 and

Ref: McGarry & Kirschner, Cell 1998, Geminin Function. Fragkos et al., Nature Rev Mol Cell Biol 2015.

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Cell Cycle Regulation

Which factor ensures that DNA replication occurs only once per cell cycle?

Guaranteeing exactly one round of DNA replication per cycle requires blocking re-loading of MCM helicases onto origins after they have fired. Two mechanisms converge. First, CDK2 phosphorylates licensing factors Cdc6 marking for SCF degradation and nuclear export, and Cdt1 phosphorylation marking for CRL4-Cdt2 ubiquitination triggered by PCNA at replication forks. Geminin provides second safeguard independent of phosphorylation. Absent in G1 because APC/C-Cdh1 ubiquitinates it, geminin begins accumulation from early S reaching high levels through G2 and M. It binds with high affinity to coiled

Ref: McGarry & Kirschner, Geminin Prevents Rereplication, Cell 1998; Arias & Walter, Mechanism of Cdt1 Regulation Preventing Rereplication.

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Replication in Prokaryotes

SeqA protein binds to

Replication produces hemimethylated GATC where parental strand remains methylated by Dam methylase but newly synthesized strand unmethylated temporarily for several minutes. SeqA protein specifically recognizes clusters of hemimethylated GATC abundant in oriC containing eleven sites. Binding sequesters oriC at membrane for roughly one third of cell cycle blocking DnaA re-binding and preventing reinitiation until Dam fully methylates origin. This sequestration mechanism enforces once-per-cycle replication and coordinates initiation timing with chromosome segregation. Fully methylated or complet

Ref: Alberts et al., Chapter 5 and Kleckner studies: SeqA binding hemimethylated oriC and sequestration timing

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