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.