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Vol. 9, Issue 1, 63-73, January 1998
Departments of Molecular Biology and Cell Biology, The Scripps
Research Institute, La Jolla, California 92037
Fission yeast Cdc18, a homologue of Cdc6 in budding yeast and
metazoans, is periodically expressed during the S phase and required
for activation of replication origins. Cdc18 overexpression induces DNA
rereplication without mitosis, as does elimination of Cdc2-Cdc13 kinase
during G2 phase. These findings suggest that illegitimate
activation of origins may be prevented through inhibition of Cdc18 by
Cdc2. Consistent with this hypothesis, we report that Cdc18 interacts
with Cdc2 in association with Cdc13 and Cig2 B-type cyclins in vivo.
Cdc18 is phosphorylated by the associated Cdc2 in vitro. Mutation of a
single phosphorylation site, T104A, activates Cdc18 in the
rereplication assay. The cdc18-K9 mutation is suppressed by a cig2 mutation, providing genetic evidence that
Cdc2-Cig2 kinase inhibits Cdc18. Moreover, constitutive expression of
Cig2 prevents rereplication in cells lacking Cdc13. These findings identify Cdc18 as a key target of Cdc2-Cdc13 and Cdc2-Cig2 kinases in
the mechanism that limits chromosomal DNA replication to once per cell
cycle.
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