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

Guo, Cai and Kumagai, Akiko and Schlacher, Katharina and Shevchenko, Anna and Shevchenko, Andrej and Dunphy, William G. (2015) Interaction of Chk1 with Treslin Negatively Regulates the Initiation of Chromosomal DNA Replication. Molecular Cell, 57 (3). pp. 492-505. ISSN 1097-2765. PMCID PMC4321788.

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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.

Item Type:Article
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URLURL TypeDescription CentralArticle
Kumagai, Akiko0000-0003-2422-8053
Dunphy, William G.0000-0001-7598-8939
Additional Information:© 2015 Elsevier Inc. Received: July 15, 2014; Revised: October 16, 2014; Accepted: November 24, 2014; Published: December 31, 2014. We are grateful to laboratory members for comments on the manuscript. We also thank Juan Ramírez-Lugo for anti-ISWI antibodies. This work was supported by NIH grants GM043974 and GM070891 to W.G.D.
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Issue or Number:3
PubMed Central ID:PMC4321788
Record Number:CaltechAUTHORS:20150108-104415668
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Official Citation:Cai Guo, Akiko Kumagai, Katharina Schlacher, Anna Shevchenko, Andrej Shevchenko, William G. Dunphy, Interaction of Chk1 with Treslin Negatively Regulates the Initiation of Chromosomal DNA Replication, Molecular Cell, Volume 57, Issue 3, 5 February 2015, Pages 492-505, ISSN 1097-2765, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:53337
Deposited By: Tony Diaz
Deposited On:08 Jan 2015 19:42
Last Modified:09 Mar 2020 13:18

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