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Published February 5, 2015 | Accepted Version + Supplemental Material
Journal Article Open

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

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.

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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Accepted Version - nihms646777.pdf

Supplemental Material - mmc1.pdf

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August 20, 2023
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