Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
EMBO J
2005 Jan 26;242:395-404. doi: 10.1038/sj.emboj.7600520.
Show Gene links
Show Anatomy links
Cdt1 downregulation by proteolysis and geminin inhibition prevents DNA re-replication in Xenopus.
Li A
,
Blow JJ
.
???displayArticle.abstract???
In late mitosis and G1, Mcm2-7 are assembled onto replication origins to 'license' them for initiation. At other cell cycle stages, licensing is inhibited, thus ensuring that origins fire only once per cell cycle. Three additional factors--the origin recognition complex, Cdc6 and Cdt1--are required for origin licensing. We examine here how licensing is regulated in Xenopus egg extracts. We show that Cdt1 is downregulated late in the cell cycle by two different mechanisms: proteolysis, which occurs in part due to the activity of the anaphase-promoting complex (APC/C), and inhibition by a protein called geminin. If both these regulatory mechanisms are abrogated, extracts undergo uncontrolled re-licensing and re-replication. The extent of re-replication is limited by checkpoint kinases that are activated as a consequence of re-replication itself. These results allow us to build a comprehensive model of how re-replication of DNA is prevented in Xenopus, with Cdt1 regulation being the key feature. The results also explain the original experiments that led to the proposal of a replication licensing factor.
Ballabeni,
Human geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis.
2004, Pubmed,
Xenbase
Ballabeni,
Human geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis.
2004,
Pubmed
,
Xenbase
Bastians,
Cell cycle-regulated proteolysis of mitotic target proteins.
1999,
Pubmed
,
Xenbase
Blow,
Control of chromosomal DNA replication in the early Xenopus embryo.
2001,
Pubmed
,
Xenbase
Blow,
Replication licensing--defining the proliferative state?
2002,
Pubmed
Blow,
A role for the nuclear envelope in controlling DNA replication within the cell cycle.
1988,
Pubmed
,
Xenbase
Blow,
Preventing re-replication of DNA in a single cell cycle: evidence for a replication licensing factor.
1993,
Pubmed
,
Xenbase
Capasso,
Phosphorylation activates Chk1 and is required for checkpoint-mediated cell cycle arrest.
2002,
Pubmed
,
Xenbase
Chong,
Purification of an MCM-containing complex as a component of the DNA replication licensing system.
1995,
Pubmed
,
Xenbase
Chong,
Characterization of the Xenopus replication licensing system.
1997,
Pubmed
,
Xenbase
Coleman,
The Xenopus Cdc6 protein is essential for the initiation of a single round of DNA replication in cell-free extracts.
1996,
Pubmed
,
Xenbase
Coverley,
Reversible effects of nuclear membrane permeabilization on DNA replication: evidence for a positive licensing factor.
1993,
Pubmed
,
Xenbase
Dilworth,
Two complexes that contain histones are required for nucleosome assembly in vitro: role of nucleoplasmin and N1 in Xenopus egg extracts.
1987,
Pubmed
,
Xenbase
Gillespie,
Nucleoplasmin-mediated chromatin remodelling is required for Xenopus sperm nuclei to become licensed for DNA replication.
2000,
Pubmed
,
Xenbase
Gillespie,
Reconstitution of licensed replication origins on Xenopus sperm nuclei using purified proteins.
2001,
Pubmed
,
Xenbase
Gopalakrishnan,
Redundant control of rereplication in fission yeast.
2001,
Pubmed
Guo,
Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts.
2000,
Pubmed
,
Xenbase
Hodgson,
Geminin becomes activated as an inhibitor of Cdt1/RLF-B following nuclear import.
2002,
Pubmed
,
Xenbase
Jares,
A Xenopus Dbf4 homolog is required for Cdc7 chromatin binding and DNA replication.
2004,
Pubmed
,
Xenbase
Kubota,
Determination of initiation of DNA replication before and after nuclear formation in Xenopus egg cell free extracts.
1993,
Pubmed
,
Xenbase
Kubota,
Identification of the yeast MCM3-related protein as a component of Xenopus DNA replication licensing factor.
1995,
Pubmed
,
Xenbase
Kubota,
Licensing of DNA replication by a multi-protein complex of MCM/P1 proteins in Xenopus eggs.
1997,
Pubmed
,
Xenbase
Lee,
Structural basis for inhibition of the replication licensing factor Cdt1 by geminin.
2004,
Pubmed
,
Xenbase
Leno,
The nuclear membrane prevents replication of human G2 nuclei but not G1 nuclei in Xenopus egg extract.
1992,
Pubmed
,
Xenbase
Li,
Non-proteolytic inactivation of geminin requires CDK-dependent ubiquitination.
2004,
Pubmed
,
Xenbase
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
Liu,
Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint.
2000,
Pubmed
Luciani,
Characterization of a novel ATR-dependent, Chk1-independent, intra-S-phase checkpoint that suppresses initiation of replication in Xenopus.
2004,
Pubmed
,
Xenbase
Madine,
MCM3 complex required for cell cycle regulation of DNA replication in vertebrate cells.
1995,
Pubmed
,
Xenbase
Mahbubani,
Cell cycle regulation of the replication licensing system: involvement of a Cdk-dependent inhibitor.
1997,
Pubmed
,
Xenbase
Maiorano,
XCDT1 is required for the assembly of pre-replicative complexes in Xenopus laevis.
2000,
Pubmed
,
Xenbase
McGarry,
Geminin deficiency causes a Chk1-dependent G2 arrest in Xenopus.
2002,
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
Nguyen,
Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms.
2001,
Pubmed
Nishitani,
Proteolysis of DNA replication licensing factor Cdt1 in S-phase is performed independently of geminin through its N-terminal region.
2004,
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,
Control of DNA replication licensing in a cell cycle.
2002,
Pubmed
,
Xenbase
Oehlmann,
The role of Cdc6 in ensuring complete genome licensing and S phase checkpoint activation.
2004,
Pubmed
,
Xenbase
Peter,
The APC is dispensable for first meiotic anaphase in Xenopus oocytes.
2001,
Pubmed
,
Xenbase
Prokhorova,
Sequential MCM/P1 subcomplex assembly is required to form a heterohexamer with replication licensing activity.
2000,
Pubmed
,
Xenbase
Quinn,
The Drosophila Geminin homolog: roles for Geminin in limiting DNA replication, in anaphase and in neurogenesis.
2001,
Pubmed
,
Xenbase
Reimann,
Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex.
2001,
Pubmed
,
Xenbase
Rowles,
Interaction between the origin recognition complex and the replication licensing system in Xenopus.
1996,
Pubmed
,
Xenbase
Sugimoto,
Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding.
2004,
Pubmed
Sun,
The replication capacity of intact mammalian nuclei in Xenopus egg extracts declines with quiescence, but the residual DNA synthesis is independent of Xenopus MCM proteins.
2000,
Pubmed
,
Xenbase
Tada,
The RLF-B component of the replication licensing system is distinct from Cdc6 and functions after Cdc6 binds to chromatin.
1999,
Pubmed
,
Xenbase
Tada,
Repression of origin assembly in metaphase depends on inhibition of RLF-B/Cdt1 by geminin.
2001,
Pubmed
,
Xenbase
Thomer,
Drosophila double-parked is sufficient to induce re-replication during development and is regulated by cyclin E/CDK2.
2004,
Pubmed
Thömmes,
The RLF-M component of the replication licensing system forms complexes containing all six MCM/P1 polypeptides.
1997,
Pubmed
,
Xenbase
Vaziri,
A p53-dependent checkpoint pathway prevents rereplication.
2003,
Pubmed
Wohlschlegel,
Inhibition of eukaryotic DNA replication by geminin binding to Cdt1.
2000,
Pubmed
,
Xenbase
Zhong,
CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing.
2003,
Pubmed
Zhu,
Rereplication by depletion of geminin is seen regardless of p53 status and activates a G2/M checkpoint.
2004,
Pubmed
