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Vol. 10, Issue 10, 3263-3277, October 1999
Braun Laboratories, California Institute of Technology, Pasadena,
California 91125
The replication initiation protein Cdc6p forms a tight
complex with Cdc28p, specifically with forms of the kinase that are competent to promote replication initiation. We now show that potential
sites of Cdc28 phosphorylation in Cdc6p are required for the regulated
destruction of Cdc6p that has been shown to occur during the
Saccharomyces cerevisiae cell cycle. Analysis of Cdc6p
phosphorylation site mutants and of the requirement for Cdc28p in an in
vitro ubiquitination system suggests that targeting of Cdc6p for
degradation is more complex than previously proposed. First,
phosphorylation of N-terminal sites targets Cdc6p for
polyubiquitination probably, as expected, through promoting interaction
with Cdc4p, an F box protein involved in substrate recognition by the
Skp1-Cdc53-F-box protein (SCF) ubiquitin ligase. However, in
addition, mutation of a single, C-terminal site stabilizes Cdc6p in G2
phase cells without affecting substrate recognition by SCF in vitro,
demonstrating a second and novel requirement for specific
phosphorylation in degradation of Cdc6p. SCF-Cdc4p- and N-terminal
phosphorylation site-dependent ubiquitination appears to be mediated
preferentially by Clbp/Cdc28p complexes rather than by Clnp/Cdc28ps,
suggesting a way in which phosphorylation of Cdc6p might control the
timing of its degradation at then end of G1 phase of the cell cycle. The stable cdc6 mutants show no apparent replication
defects in wild-type strains. However, stabilization through mutation
of three N-terminal phosphorylation sites or of the single C-terminal phosphorylation site leads to dominant lethality when combined with
certain mutations in the anaphase-promoting complex.
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