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.
Mol Biol Cell
2009 Feb 01;203:937-47. doi: 10.1091/mbc.e08-06-0613.
Show Gene links
Show Anatomy links
Repression of nascent strand elongation by deregulated Cdt1 during DNA replication in Xenopus egg extracts.
Tsuyama T
,
Watanabe S
,
Aoki A
,
Cho Y
,
Seki M
,
Enomoto T
,
Tada S
.
???displayArticle.abstract???
Excess Cdt1 reportedly induces rereplication of chromatin in cultured cells and Xenopus egg extracts, suggesting that the regulation of Cdt1 activity by cell cycle-dependent proteolysis and expression of the Cdt1 inhibitor geminin is crucial for the inhibition of chromosomal overreplication between S phase and metaphase. We analyzed the consequences of excess Cdt1 for DNA replication and found that increased Cdt1 activity inhibited the elongation of nascent strands in Xenopus egg extracts. In Cdt1-supplemented extracts, overreplication was remarkably induced by the further addition of the Cdt1-binding domain of geminin (Gem79-130), which lacks licensing inhibitor activity. Further analyses indicated that fully active geminin, as well as Gem79-130, restored nascent strand elongation in Cdt1-supplemented extracts even after the Cdt1-induced stalling of replication fork elongation had been established. Our results demonstrate an unforeseen, negative role for Cdt1 in elongation and suggest that its function in the control of replication should be redefined. We propose a novel surveillance mechanism in which Cdt1 blocks nascent chain elongation after detecting illegitimate activation of the licensing system.
Abraham,
Cell cycle checkpoint signaling through the ATM and ATR kinases.
2001, Pubmed
Abraham,
Cell cycle checkpoint signaling through the ATM and ATR kinases.
2001,
Pubmed
Archambault,
Disruption of mechanisms that prevent rereplication triggers a DNA damage response.
2005,
Pubmed
Arias,
Replication-dependent destruction of Cdt1 limits DNA replication to a single round per cell cycle in Xenopus egg extracts.
2005,
Pubmed
,
Xenbase
Arias,
PCNA functions as a molecular platform to trigger Cdt1 destruction and prevent re-replication.
2006,
Pubmed
,
Xenbase
Arias,
Strength in numbers: preventing rereplication via multiple mechanisms in eukaryotic cells.
2007,
Pubmed
Bartkova,
Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints.
2006,
Pubmed
Blow,
Preventing re-replication of chromosomal DNA.
2005,
Pubmed
Chong,
Characterization of the Xenopus replication licensing system.
1997,
Pubmed
,
Xenbase
Claycomb,
Visualization of replication initiation and elongation in Drosophila.
2002,
Pubmed
Davidson,
Deregulated replication licensing causes DNA fragmentation consistent with head-to-tail fork collision.
2006,
Pubmed
,
Xenbase
Di Micco,
Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication.
2006,
Pubmed
Diffley,
Regulation of early events in chromosome replication.
2004,
Pubmed
,
Xenbase
Fujita,
Cdt1 revisited: complex and tight regulation during the cell cycle and consequences of deregulation in mammalian cells.
2006,
Pubmed
Fukuda,
Structure-function relationship of the eukaryotic DNA replication factor, proliferating cell nuclear antigen.
1995,
Pubmed
Hashimoto,
Xenopus Cut5 is essential for a CDK-dependent process in the initiation of DNA replication.
2003,
Pubmed
,
Xenbase
Hodgson,
Geminin becomes activated as an inhibitor of Cdt1/RLF-B following nuclear import.
2002,
Pubmed
,
Xenbase
Karakaidos,
Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas: synergistic effect with mutant p53 on tumor growth and chromosomal instability--evidence of E2F-1 transcriptional control over hCdt1.
2004,
Pubmed
Kerns,
Geminin prevents rereplication during xenopus development.
2007,
Pubmed
,
Xenbase
Kumagai,
The Xenopus Chk1 protein kinase mediates a caffeine-sensitive pathway of checkpoint control in cell-free extracts.
1998,
Pubmed
,
Xenbase
Kumata,
Possible involvement of RecQL4 in the repair of double-strand DNA breaks in Xenopus egg extracts.
2007,
Pubmed
,
Xenbase
Lee,
Structural basis for inhibition of the replication licensing factor Cdt1 by geminin.
2004,
Pubmed
,
Xenbase
Lee,
The Mre11/Rad50/Nbs1 complex plays an important role in the prevention of DNA rereplication in mammalian cells.
2007,
Pubmed
Li,
Non-proteolytic inactivation of geminin requires CDK-dependent ubiquitination.
2004,
Pubmed
,
Xenbase
Li,
Cdt1 downregulation by proteolysis and geminin inhibition prevents DNA re-replication in Xenopus.
2005,
Pubmed
,
Xenbase
Lin,
ATR pathway is the primary pathway for activating G2/M checkpoint induction after re-replication.
2007,
Pubmed
Liontos,
Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior.
2007,
Pubmed
Liu,
The ATR-mediated S phase checkpoint prevents rereplication in mammalian cells when licensing control is disrupted.
2007,
Pubmed
Lovejoy,
DDB1 maintains genome integrity through regulation of Cdt1.
2006,
Pubmed
Luciani,
Characterization of a novel ATR-dependent, Chk1-independent, intra-S-phase checkpoint that suppresses initiation of replication in Xenopus.
2004,
Pubmed
,
Xenbase
Maiorano,
Recombinant Cdt1 induces rereplication of G2 nuclei in Xenopus egg extracts.
2005,
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
Nishitani,
Proteolysis of DNA replication licensing factor Cdt1 in S-phase is performed independently of geminin through its N-terminal region.
2004,
Pubmed
Nishitani,
Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis.
2006,
Pubmed
Nishitani,
The Cdt1 protein is required to license DNA for replication in fission yeast.
2000,
Pubmed
Pacek,
A requirement for MCM7 and Cdc45 in chromosome unwinding during eukaryotic DNA replication.
2004,
Pubmed
,
Xenbase
Saxena,
A dimerized coiled-coil domain and an adjoining part of geminin interact with two sites on Cdt1 for replication inhibition.
2004,
Pubmed
,
Xenbase
Senga,
PCNA is a cofactor for Cdt1 degradation by CUL4/DDB1-mediated N-terminal ubiquitination.
2006,
Pubmed
Seo,
Cdt1 transgenic mice develop lymphoblastic lymphoma in the absence of p53.
2005,
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
Takeda,
Degradation of Cdt1 during S phase is Skp2-independent and is required for efficient progression of mammalian cells through S phase.
2005,
Pubmed
Teer,
Human Cdt1 lacking the evolutionarily conserved region that interacts with MCM2-7 is capable of inducing re-replication.
2008,
Pubmed
Tsuyama,
Chromatin loading of Smc5/6 is induced by DNA replication but not by DNA double-strand breaks.
2006,
Pubmed
,
Xenbase
Tsuyama,
Licensing for DNA replication requires a strict sequential assembly of Cdc6 and Cdt1 onto chromatin in Xenopus egg extracts.
2005,
Pubmed
,
Xenbase
Vaziri,
A p53-dependent checkpoint pathway prevents rereplication.
2003,
Pubmed
Waga,
DNA polymerase epsilon is required for coordinated and efficient chromosomal DNA replication in Xenopus egg extracts.
2001,
Pubmed
,
Xenbase
Whittaker,
Drosophila double parked: a conserved, essential replication protein that colocalizes with the origin recognition complex and links DNA replication with mitosis and the down-regulation of S phase transcripts.
2000,
Pubmed
Wohlschlegel,
Inhibition of eukaryotic DNA replication by geminin binding to Cdt1.
2000,
Pubmed
,
Xenbase
Yanow,
Expression of Cdc18/Cdc6 and Cdt1 during G2 phase induces initiation of DNA replication.
2001,
Pubmed
Yoshida,
Intrinsic nuclear import activity of geminin is essential to prevent re-initiation of DNA replication in Xenopus eggs.
2005,
Pubmed
,
Xenbase
