2005
DOI: 10.1242/jcs.02534
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Levels of the origin-binding protein Double parked and its inhibitor Geminin increase in response to replication stress

Abstract: The regulation of a pre-replicative complex (pre-RC) at origins ensures that the genome is replicated only once per cell cycle. Cdt1 is an essential component of the pre-RC that is rapidly degraded at G1-S and also inhibited by Geminin (Gem) protein to prevent re-replication. We have previously shown that destruction of the Drosophila homolog of Cdt1, Double-parked (Dup), at G1-S is dependent upon cyclin-E/CDK2 and important to prevent re-replication and cell death. Dup is phosphorylated by cyclin-E/Cdk2, but … Show more

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Cited by 23 publications
(27 citation statements)
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References 94 publications
(133 reference statements)
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“…In vertebrates, Cdt1 destruction is mediated by two independent and apparently redundant mechanisms: direct Cdk2 phosphorylation that targets Cdt1 to SCF SKP2 , and binding of PCNA to the Cdt1/Dup amino-terminus that targets Cdt1 to Cul4 DDB1 Nishitani et al, 2006;Senga et al, 2006). This latter result is consistent with a recent study indicating that Drosophila Dup hyperaccumulates in cells where DNA synthesis is attenuated (May et al, 2005). Thus, more than one E3 ubiquitin ligase may participate in E2f1 destruction (Ohta and Xiong, 2001).…”
Section: Mechanisms Of Cell Cycle-regulated E2f1 Destructionsupporting
confidence: 88%
“…In vertebrates, Cdt1 destruction is mediated by two independent and apparently redundant mechanisms: direct Cdk2 phosphorylation that targets Cdt1 to SCF SKP2 , and binding of PCNA to the Cdt1/Dup amino-terminus that targets Cdt1 to Cul4 DDB1 Nishitani et al, 2006;Senga et al, 2006). This latter result is consistent with a recent study indicating that Drosophila Dup hyperaccumulates in cells where DNA synthesis is attenuated (May et al, 2005). Thus, more than one E3 ubiquitin ligase may participate in E2f1 destruction (Ohta and Xiong, 2001).…”
Section: Mechanisms Of Cell Cycle-regulated E2f1 Destructionsupporting
confidence: 88%
“…This allows Cyclin E/cdk2 to phosphorylate Cdt1/Dup, leading to its degradation. 16 This model also fits well with the observations that fluctuation of CyclinE/ cdk2 activities is required for progression of endocycles 17,18 and that constitutive Cyclin E expression first induces and then inhibits endoreplication. [19][20][21] It appears as if endocycling cells single-mindedly pursue the mission of polyploidy: they eliminate mitosis by shutting down mitotic cyclin activities, 22,23 eliminate cell cycle arrest by shutting down checkpoint pathways to go through multi-round of replication with under-replicated heterochromatin (reviewed in refs.…”
supporting
confidence: 82%
“…CycE-Cdk2 then enhances its own activity by inhibiting the E2F1 repressor Rbf (Du et al 1996) resulting in a sharp peak of Cdk2 activity, which eventually triggers S-phase entry. The onset of DNA replication in turn initiates a negative feedback loop that downregulates E2F1 activity and simultaneously triggers dup/ Cdt1 degradation (May et al 2005). The short half-live of CycE mRNA and protein would then suffice to cause a drop in CycE-Cdk2 activity after completion of DNA replication (Fig.…”
Section: Discussionmentioning
confidence: 99%