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DTL (show DTL Proteins) promotes genomic stability through two distinct mechanisms. First, it is an essential component of the CUL4-DDB1 complex that controls CDT1 levels, thereby preventing rereplication. Second, it is required for the early G2/M checkpoint.
Results show that both Cdc6 (show CDC6 Proteins) and Cdt1, when expressed in a high level, alone or in combination, were significantly associated with poorer survival in the breast cancer patient cohort. In line with this finding, the expression of Cdc6 (show CDC6 Proteins) and Cdt1 was upregulated in breast cancer cells compared to normal breast epithelial cells. Expression of Cdc6 (show CDC6 Proteins) and Cdt1 was significantly higher in ER negative breast cancer.
CDT1, MCM7 (show MCM7 Proteins), and NUDT1 (show NUDT1 Proteins) were shown to be up-regulated in hepatocellular carcinoma tissues and provide a more accurate diagnosis than alpha-fetal protein alone.
PPP2R3B (show PPP2R3B Proteins) codes for the PR70 protein, a regulatory substrate-recognizing subunit of protein phosphatase 2A. PR70 decreased melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing CDC6 (show CDC6 Proteins)-chromatin licensing and CDT1 interaction
USP37 (show USP37 Proteins) interacts with Cdt1 and is able to de-ubiquitinate Cdt1 in vivo and, USP37 (show USP37 Proteins) is able to regulate the loading of MCM complexes onto the chromatin.
mismatch repair (MMR (show MRC1 Proteins)) proteins are also involved in the degradation of Cdt1 after ultraviolet irradiation in the G1 phase
Cdt1-binding protein GRWD1 promotes chromatin fluidity by influencing nucleosome structures, e.g., by transient eviction of H2A-H2B, and thereby promotes efficient MCM loading at replication origins.
ATM (show ATM Proteins) silencing induced partial reduction in levels of Skp2, a component of SCF (show KITLG Proteins)(Skp2) ubiquitin ligase that controls Cdt1 degradation.
FBXO31 (show FBXO5 Proteins) interacts with Cdt1 and regulates the degradation of Cdt1 in G2 phase.
Protein levels of Geminin (show GMNN Proteins) and Cdt1 are tightly regulated through the cell cycle, and the Cdt1-Geminin (show GMNN Proteins) complex likely acts as a molecular switch that can enable or disable the firing of each origin of replication.
These results demonstrate an important role for Cdt1 in human papillomavirus E7-induced rereplication and shed light on mechanisms by which human papillomavirus induces genomic instability.
conserved arginine residues play critical roles in interaction with Geminin (show GMNN Proteins) and Mcm that are crucial for proper conformation of the complexes and its licensing activity.
Study shows that ablation of Geminin (show GMNN Proteins) induces massive rereplication as a result of unrestrained Cdt1 activity in embryonic stem cells, whereas it has no such effect in embryonic fibroblasts in which alternative regulation of Cdt1 activity is intact.
This study reveals a conserved new regulatory Cdt1 domain crucial for proper DNA licensing activity.
Structure and mutagenesis studies of the C-terminal region of licensing factor Cdt1 enable the identification of key residues for binding to replicative helicase Mcm proteins.
Determined the structures of mCdt1CS (mCdt1C_small; residues 452 to 557) and mCdt1CL (mCdt1C_large; residues 420 to 557) using X-ray crystallography and NMR. This study reveals that Cdt1 is formed with a tandem repeat of the winged helix domain.
Cdt1 function is negatively regulated by the Cdk (show CDK4 Proteins) phosphorylation independent of geminin (show GMNN Proteins) binding
crystal structure of the mouse geminin (show GMNN Proteins)-Cdt1 complex using tGeminin (residues 79-157, truncated geminin (show GMNN Proteins)) and tCdt1 (residues 172-368, truncated Cdt1)
In situ hybridization and immunohistochemistry localize Cdt1 as well as geminin (show GMNN Proteins) to the proliferative compartment of the developing mouse gut (show GUSB Proteins) epithelium
Cdt1 expression characterizes progenitor cells in G1 phase
These results suggested that, at least in vitro, oleic acid-containing cell membranes of the lipid bilayer inhibit Cdt1-geminin (show GMNN Proteins) complex formation by binding to Cdt1 and thereby liberating Cdt1 from inhibition by geminin (show GMNN Proteins).
The results showed that the Cdt1 region spanning amino acids (a. a.) 255-620 is required for efficient inhibition of DNA replication, and that, within this region, a. a. 255-289 have a critical role in inhibition.
These findings suggested that excess Cdt1 suppressed the progression of replication forks.
Dynamic interactions of high Cdt1 and geminin (show GMNN Proteins) levels regulate S phase in early Xenopus embryos.
p97 (show vcp Proteins) is an essential regulator of DNA damage-dependent CDT1 destruction
CDC-48/p97 (show vcp Proteins) coordinates CDT-1 degradation with GINS chromatin dissociation to ensure faithful DNA replication
Loading of geminin (show GMNN Proteins) onto chromatin requires Cdt1, suggesting that geminin (show GMNN Proteins) is targeted at replication origins.
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
Removal of Cdt1 from chromatin and its nuclear exclusion in G2 is critical in regulating licensing and limiting DNA replication in S phase to only one round.
Cdt1 and DDB1 interact in extracts, and DDB1 chromatin loading is dependent on the binding of Cdt1 to PCNA, which indicates that PCNA docking activates the pre-formed Cdt1-Cul4(DDB1) ligase complex.
The protein encoded by this gene is involved in the formation of the pre-replication complex that is necessary for DNA replication. The encoded protein can bind geminin, which prevents replication and may function to prevent this protein from initiating replication at inappropriate origins. Phosphorylation of this protein by cyclin A-dependent kinases results in degradation of the protein.
chromatin licensing and DNA replication factor 1
, DNA replication factor Cdt1-like
, DNA replication factor Cdt1
, Double parked, Drosophila, homolog of
, double parked homolog
, retroviral insertion site 2 protein
, retroviral integration site 1
, retroviral integration site 2
, DNA replication factor