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Mol Cell. 2015 Feb 5;57(3):492-505. doi: 10.1016/j.molcel.2014.12.003. Epub 2014 Dec 31.

Interaction of Chk1 with Treslin negatively regulates the initiation of chromosomal DNA replication.

Author information

1
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
2
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA; Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
3
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
4
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: dunphy@caltech.edu.

Abstract

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.

PMID:
25557548
PMCID:
PMC4321788
DOI:
10.1016/j.molcel.2014.12.003
[Indexed for MEDLINE]
Free PMC Article

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