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EMBO J
2004 Aug 04;2315:3122-32. doi: 10.1038/sj.emboj.7600314.
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Human geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis.
Ballabeni A
,
Melixetian M
,
Zamponi R
,
Masiero L
,
Marinoni F
,
Helin K
.
???displayArticle.abstract??? Geminin is an unstable inhibitor of DNA replication that negatively regulates the licensing factor CDT1 and inhibits pre-replicative complex (pre-RC) formation in Xenopus egg extracts. Here we describe a novel function of Geminin. We demonstrate that human Geminin protects CDT1 from proteasome-mediated degradation by inhibiting its ubiquitination. In particular, Geminin ensures basal levels of CDT1 during S phase and its accumulation during mitosis. Consistently, inhibition of Geminin synthesis during M phase leads to impairment of pre-RC formation and DNA replication during the following cell cycle. Moreover, we show that inhibition of CDK1 during mitosis, and not Geminin depletion, is sufficient for premature formation of pre-RCs, indicating that CDK activity is the major mitotic inhibitor of licensing in human cells. Taken together with recent data from our laboratory, our results demonstrate that Geminin is both a negative and positive regulator of pre-RC formation in human cells, playing a positive role in allowing CDT1 accumulation in G2-M, and preventing relicensing of origins in S-G2.
Bastians,
Cell cycle-regulated proteolysis of mitotic target proteins.
1999,
Pubmed
,
Xenbase
Bielinsky,
Replication origins: why do we need so many?
2003,
Pubmed
Bousset,
The Cdc7 protein kinase is required for origin firing during S phase.
1998,
Pubmed
Cocker,
An essential role for the Cdc6 protein in forming the pre-replicative complexes of budding yeast.
1996,
Pubmed
Dahmann,
S-phase-promoting cyclin-dependent kinases prevent re-replication by inhibiting the transition of replication origins to a pre-replicative state.
1995,
Pubmed
DePamphilis,
The 'ORC cycle': a novel pathway for regulating eukaryotic DNA replication.
2003,
Pubmed
Del Bene,
Direct interaction of geminin and Six3 in eye development.
2004,
Pubmed
,
Xenbase
Diffley,
Stepwise assembly of initiation complexes at budding yeast replication origins during the cell cycle.
1995,
Pubmed
Diffley,
Once and only once upon a time: specifying and regulating origins of DNA replication in eukaryotic cells.
1996,
Pubmed
Dimitrova,
Mammalian nuclei become licensed for DNA replication during late telophase.
2002,
Pubmed
,
Xenbase
Donaldson,
Cdc7 is required throughout the yeast S phase to activate replication origins.
1998,
Pubmed
Donovan,
Cdc6p-dependent loading of Mcm proteins onto pre-replicative chromatin in budding yeast.
1997,
Pubmed
,
Xenbase
Frouin,
Cell cycle-dependent dynamic association of cyclin/Cdk complexes with human DNA replication proteins.
2002,
Pubmed
Gilbert,
Making sense of eukaryotic DNA replication origins.
2001,
Pubmed
Hodgson,
Geminin becomes activated as an inhibitor of Cdt1/RLF-B following nuclear import.
2002,
Pubmed
,
Xenbase
Jallepalli,
Cyclin-dependent kinase and initiation at eukaryotic origins: a replication switch?
1997,
Pubmed
Jiang,
Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication.
1999,
Pubmed
Kondo,
Rapid degradation of Cdt1 upon UV-induced DNA damage is mediated by SCFSkp2 complex.
2004,
Pubmed
Krude,
Cyclin/Cdk-dependent initiation of DNA replication in a human cell-free system.
1997,
Pubmed
Labib,
MCM2-7 proteins are essential components of prereplicative complexes that accumulate cooperatively in the nucleus during G1-phase and are required to establish, but not maintain, the S-phase checkpoint.
2001,
Pubmed
Lei,
Initiating DNA synthesis: from recruiting to activating the MCM complex.
2001,
Pubmed
Li,
The SCF(Skp2) ubiquitin ligase complex interacts with the human replication licensing factor Cdt1 and regulates Cdt1 degradation.
2003,
Pubmed
Liu,
Cyclin-dependent kinases phosphorylate human Cdt1 and induce its degradation.
2004,
Pubmed
Luo,
The cell-cycle regulator geminin inhibits Hox function through direct and polycomb-mediated interactions.
2004,
Pubmed
Lupas,
Predicting coiled coils from protein sequences.
1991,
Pubmed
Maiorano,
XCDT1 is required for the assembly of pre-replicative complexes in Xenopus laevis.
2000,
Pubmed
,
Xenbase
McGarry,
Geminin, an inhibitor of DNA replication, is degraded during mitosis.
1998,
Pubmed
,
Xenbase
Melixetian,
Loss of Geminin induces rereplication in the presence of functional p53.
2004,
Pubmed
Mihaylov,
Control of DNA replication and chromosome ploidy by geminin and cyclin A.
2002,
Pubmed
Nishitani,
The Cdt1 protein is required to license DNA for replication in fission yeast.
2000,
Pubmed
Nishitani,
The human licensing factor for DNA replication Cdt1 accumulates in G1 and is destabilized after initiation of S-phase.
2001,
Pubmed
,
Xenbase
Nishitani,
Proteolysis of DNA replication licensing factor Cdt1 in S-phase is performed independently of geminin through its N-terminal region.
2004,
Pubmed
Noton,
CDK inactivation is the only essential function of the APC/C and the mitotic exit network proteins for origin resetting during mitosis.
2000,
Pubmed
Nougarède,
Hierarchy of S-phase-promoting factors: yeast Dbf4-Cdc7 kinase requires prior S-phase cyclin-dependent kinase activation.
2000,
Pubmed
Okuno,
Stability, chromatin association and functional activity of mammalian pre-replication complex proteins during the cell cycle.
2001,
Pubmed
,
Xenbase
Petersen,
Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1.
2000,
Pubmed
Petersen,
Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization.
1999,
Pubmed
Rowley,
Initiation complex assembly at budding yeast replication origins begins with the recognition of a bipartite sequence by limiting amounts of the initiator, ORC.
1995,
Pubmed
Seki,
Stepwise assembly of initiation proteins at budding yeast replication origins in vitro.
2000,
Pubmed
Stoeber,
DNA replication licensing and human cell proliferation.
2001,
Pubmed
Sugimoto,
Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding.
2004,
Pubmed
Tada,
Repression of origin assembly in metaphase depends on inhibition of RLF-B/Cdt1 by geminin.
2001,
Pubmed
,
Xenbase
Weinreich,
Binding of cyclin-dependent kinases to ORC and Cdc6p regulates the chromosome replication cycle.
2001,
Pubmed
Wohlschlegel,
Inhibition of eukaryotic DNA replication by geminin binding to Cdt1.
2000,
Pubmed
,
Xenbase
Woo,
Cyclin-dependent kinases and S phase control in mammalian cells.
2003,
Pubmed
,
Xenbase
Wyrick,
Genome-wide distribution of ORC and MCM proteins in S. cerevisiae: high-resolution mapping of replication origins.
2001,
Pubmed
Yanagi,
Mouse geminin inhibits not only Cdt1-MCM6 interactions but also a novel intrinsic Cdt1 DNA binding activity.
2002,
Pubmed
Zou,
Formation of a preinitiation complex by S-phase cyclin CDK-dependent loading of Cdc45p onto chromatin.
1998,
Pubmed
