Chen YC, Weinreich M

Cdc7-Dbf4 is a conserved, two-subunit kinase required for initiating eukaryotic DNA replication. Recent studies have shown that Cdc7-Dbf4 also regulates the mitotic exit network (MEN) and monopolar homolog orientation in meiosis I (1, 2). Both activities likely involve a Cdc7-Dbf4 interaction with Cdc5, the single Polo-like kinase in budding yeast. ...

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We previously showed that Dbf4 binds the Cdc5 polo-box domain (PBD) via a ~40 residue N-terminal sequence, which lacks a PBD consensus binding site (S(pS/pT)P/X), and that Dbf4 inhibits Cdc5 function during mitosis. Here we identify a non-consensus PBD binding site within Dbf4 and demonstrate that the PBD-Dbf4 interaction occurs via a distinct PBD surface from that used to bind phospho-proteins. Genetic and biochemical analysis of multiple dbf4 mutants indicates that Dbf4 inhibits Cdc5 function through direct binding. Surprisingly, mutation of invariant Cdc5 residues required for binding phosphorylated substrates has little effect on yeast viability or growth rate. Instead, cdc5 mutants defective for binding phospho-proteins exhibit enhanced resistance to microtubule disruption and an increased rate of spindle elongation. This study therefore details the molecular nature of a new type of PBD binding and reveals that Cdc5 targeting to phosphorylated substrates likely regulates spindle dynamics.

Date: Oct. 29, 2010

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