A conserved proliferating cell nuclear antigen-interacting protein sequence in Chk1 is required for checkpoint function

Scorah, J., Dong, M.-Q., Yates, J.R., Scott, M. , Gillespie, D. and McGowan, C.H. (2008) A conserved proliferating cell nuclear antigen-interacting protein sequence in Chk1 is required for checkpoint function. Journal of Biological Chemistry, 283(25), pp. 17250-17259. (doi: 10.1074/jbc.M800369200)

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Abstract

Human checkpoint kinase 1 (Chk1) is an essential kinase required for cell cycle checkpoints and for coordination of DNA synthesis. To gain insight into the mechanisms by which Chk1 carries out these functions, we used mass spectrometry to identify previously uncharacterized interacting partners of Chk1. We describe a novel interaction between Chk1 and proliferating cell nuclear antigen (PCNA), an essential component of the replication machinery. Binding between Chk1 and PCNA was reduced in the presence of hydroxyurea, suggesting that the interaction is regulated by replication stress. A highly conserved PCNA-interacting protein (PIP) box motif was identified in Chk1. The intact PIP box is required for efficient DNA damage-induced phosphorylation and release of activated Chk1 from chromatin. We find that the PIP box of Chk1 is crucial for Chk1-mediated S-M and G2-M checkpoint responses. In addition, we show that mutations in the PIP box of Chk1 lead to decreased rates of replication fork progression and increased aberrant replication. These findings suggest an additional mechanism by which essential components of the DNA replication machinery interact with the replication checkpoint apparatus.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Scott, Dr Mary and Gillespie, Professor David
Authors: Scorah, J., Dong, M.-Q., Yates, J.R., Scott, M., Gillespie, D., and McGowan, C.H.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Journal of Biological Chemistry
Journal Abbr.:J Biol Chem.
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN:0021-9258
ISSN (Online):1083-351X
Published Online:30 April 2008

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