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Fig. 6. A model for Dup degradation during S phase. (A) Summary of proteins and activities at origins and forks that were tested and found to be required for normal Dup degradation. Only the origin and replication-fork proteins that were tested are shown, except for the pre-RC protein CDC6, which was not tested. HU inhibits polymerase indirectly by inhibiting ribonucleotide reductase, which results in depletion of dNTPs. (B) Dup degradation during a normal S phase. We had previously shown that cyclin-E/CDK2 is indirectly required for Dup degradation (Thomer et al., 2004). Cyclin-E/CDK2 phosphorylates Dup but the relative contribution of this modification to the instability of Dup appears to be relatively minor (dotted arrow). Based on current evidence, we propose that DNA replication is the CDK2-dependent activity that is required for Dup degradation. This might be required to promote ubiquitylation of Dup by an unknown ubiquitin (Ub) ligase, leading to the rapid destruction of Dup at the proteasome. (C) When CDK2 activity is inhibited (Thomer et al., 2004) or other problems with DNA replication are encountered (this study), Dup is not degraded, perhaps because of reduced ubiquitylation. Because Dup mRNA continues to be translated, Dup accumulates to high levels. Replication stress also results in an increase in Gem levels, which probably plays a prominent role in preventing the relicensing of origins when Dup degradation fails
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