Abstract
The budding yeast Dbf4-dependent kinase (DDK) complex—comprised of cell division cycle (Cdc7) kinase and its regulatory subunit dumbbell former 4 (Dbf4)—is required to trigger the initiation of DNA replication through the phosphorylation of multiple minichromosome maintenance complex subunits 2-7 (Mcm2-7). DDK is also a target of the radiation sensitive 53 (Rad53) checkpoint kinase in response to replication stress. Numerous investigations have determined mechanistic details, including the regions of Mcm2, Mcm4, and Mcm6 phosphorylated by DDK, and a number of DDK docking sites. Similarly, the way in which the Rad53 forkhead-associated 1 (FHA1) domain binds to DDK—involving both canonical and non-canonical interactions—has been elucidated. Recent work has revealed mutual promotion of DDK and synthetic lethal with dpb11-1 3 (Sld3) roles. While DDK phosphorylation of Mcm2-7 subunits facilitates their interaction with Sld3 at origins, Sld3 in turn stimulates DDK phosphorylation of Mcm2. Details of a mutually antagonistic relationship between DDK and Rap1-interacting factor 1 (Rif1) have also recently come to light. While Rif1 is able to reverse DDK-mediated Mcm2-7 complex phosphorylation by targeting the protein phosphatase glycogen 7 (Glc7) to origins, there is evidence to suggest that DDK can counteract this activity by binding to and phosphorylating Rif1.
Highlights
In an unperturbed cell cycle, budding yeast dumbbell former 4 (Dbf4)-dependent kinase (DDK) complex triggers the initiation of DNA replication mainly through the phosphorylation of minichromosome maintenance complex subunits 2-7 (Mcm2-7)
Activity (CDK) to generate events carried out by Dbf4-dependent kinase (DDK) and cyclin-dependent kinase is low until the end of G1 phase, as Dbf4—the regulatory subunit of DDK—is degraded in an the active form of the CMG (Cdc45-Mcm2-7-go-ichi-ni-san(GINS)) helicase
Dbf4 localization at centromeres has been observed in human cells, and DDK was implicated in regulating the recruitment of topoisomerase 2-alpha (TOP2A), which is required for chromosome condensation and sister chromatid separation [81]
Summary
In an unperturbed cell cycle, budding yeast Dbf4-dependent kinase (DDK) complex triggers the initiation of DNA replication mainly through the phosphorylation of minichromosome maintenance complex subunits 2-7 (Mcm2-7) (reviewed in [1]). A much better understanding of the way in which DDK associates with both Mcm and Rad (structurally and functionally) has been gained. Roles for additional protein factors in regulating DDK stimulation have been uncovered. These include synthetic lethal with dpb (Sld3), which both stimulates DDK phosphorylation of Mcm and binds to DDK-phosphorylated Mcm and Mcm; and Rap1-interacting factor 1 (Rif1), which counteracts DDK activity by recruiting the protein phosphatase glycogen 7 (Glc). Evidence supporting a role for DDK in coordinating the initiation of DNA replication with sister chromatid cohesion will be discussed
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