hide
Free keywords:
DNA replication initiation Origin firing Cell cycle regulation Temporal program of replication DNA damage checkpoint
Abstract:
Replication initiation in eukaryotes is subdivided into two phases—origin licensing and origin firing. These phases have opposite requirements for cyclin-dependent kinase (CDK) phosphorylation and are therefore restricted to different cell cycle phases: origin licensing occurs in the absence of CDK activity (G1 phase) and results in the formation of inactive precursors of the replicative DNA helicase at origins of replication. Origin firing occurs upon CDK activation in S phase and results in the activation of the replicative helicase.
Central to the control of origin firing is a three-partite protein complex, which was first identified in budding yeast, but is apparently conserved among eukaryotes, and consists of Sld3, Dpb11, and Sld2 (SDS complex). Both Sld3 and Sld2 bind to Dpb11 in a CDK-phosphorylation-dependent manner and together form the minimal set of CDK substrates required for origin firing. The SDS complex facilitates helicase activation by promoting the association of accessory helicase subunits (Cdc45 and GINS complex) to form the CMG helicase. Importantly, the SDS complex-mediated CMG formation is a central element to various aspects of replication control, such as the temporal replication program and the regulation of origin firing by the checkpoint.
