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Interaction of Chk1 with Treslin Negatively Regulates the Initiation of Chromosomal DNA Replication

Guo, Cai ; Kumagai, Akiko ; Schlacher, Katharina ; Shevchenko, Anna ; Shevchenko, Andrej ; Dunphy, William G.

Molecular cell, 2015-02, Vol.57 (3), p.492-505 [Periódico revisado por pares]

United States: Elsevier Inc

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  • Título:
    Interaction of Chk1 with Treslin Negatively Regulates the Initiation of Chromosomal DNA Replication
  • Autor: Guo, Cai ; Kumagai, Akiko ; Schlacher, Katharina ; Shevchenko, Anna ; Shevchenko, Andrej ; Dunphy, William G.
  • Assuntos: Animals ; Binding Sites ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Cell Line, Tumor ; Checkpoint Kinase 1 ; Chromosomes - metabolism ; DNA Replication ; HEK293 Cells ; Humans ; Phosphorylation ; Protein Kinases - metabolism ; Xenopus laevis - embryology ; Xenopus laevis - genetics ; Xenopus laevis - metabolism ; Xenopus Proteins - genetics ; Xenopus Proteins - metabolism
  • É parte de: Molecular cell, 2015-02, Vol.57 (3), p.492-505
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
    Present Address: Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX 77054, USA
  • Descrição: Treslin helps to trigger the initiation of DNA replication by promoting integration of Cdc45 into the replicative helicase. Treslin is a key positive-regulatory target of cell-cycle control mechanisms; activation of Treslin by cyclin-dependent kinase is essential for the initiation of replication. Here we demonstrate that Treslin is also a critical locus for negative regulatory mechanisms that suppress initiation. We found that the checkpoint-regulatory kinase Chk1 associates specifically with a C-terminal domain of Treslin (designated TRCT). Mutations in the TRCT domain abolish binding of Chk1 to Treslin and thereby eliminate Chk1-catalyzed phosphorylation of Treslin. Significantly, abolition of the Treslin-Chk1 interaction results in elevated initiation of chromosomal DNA replication during an unperturbed cell cycle, which reveals a function for Chk1 during a normal S phase. This increase is due to enhanced loading of Cdc45 onto potential replication origins. These studies provide important insights into how vertebrate cells orchestrate proper initiation of replication. [Display omitted] •Chk1 binds to a C-terminal region of Treslin called the TRCT domain•Mutations in the TRCT domain abolish phosphorylation of Treslin by Chk1•Disruption of the Treslin-Chk1 interaction increases initiation of DNA replication•Chk1 regulates Treslin during an apparently normal S phase In vertebrates, Treslin is necessary for activation of the replicative helicase and the ensuing initiation of DNA replication. Previous studies have indicated that S phase cyclin-dependent kinase activity positively regulates the action of Treslin. Guo et al. now demonstrate that the checkpoint-regulatory kinase Chk1 negatively regulates the initiation-promoting function of Treslin.
  • Editor: United States: Elsevier Inc
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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