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Vol. 16, No. 10, pp. 1182-1194, May 15, 2002
Division of Biology, University of California, San Diego,
La Jolla, California 92093-0349, USA
CDK2 activity is regulated by phosphorylation/dephosphorylation,
subcellular localization, cyclin levels, and cyclin dependent kinase
inhibitors (CKIs). Using Xenopus egg extracts, we find that
degradation of Xic1, a Xenopus
p21cip1/p27kip1 family member, is coupled to
initiation of DNA replication. Xic1 turnover requires the formation of
a prereplication complex (pre-RC). Additionally, downstream initiation
factors including CDK2, Cdc7, and Cdc45, but not RPA or DNA polymerase
, are necessary for activating the degradation system. Xic1
degradation is attenuated following completion of DNA replication.
Unlike degradation of p27kip1 in mammalian cells, CDK2
activity is not directly involved in Xic1 degradation and interactions
between Xic1 and CDK2/cyclin E are dispensable for Xic1 turnover.
Interestingly, a C-terminal region (162-192) of Xic1 is essential and
apparently sufficient for triggering Xic1 ubiquitination prior to
degradation. These observations demonstrate that a direct link exists
between DNA replication and CKI degradation.
[Key Words: CDK inhibitor; Xic1; initiation of DNA replication; CDK2/cyclin E]
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