Cleavage of claspin by caspase-7 during apoptosis inhibits the CHK1 pathway

doi:10.1074/jbc.M506460200

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Papers In Press, published online ahead of print August 25, 2005
J. Biol. Chem, 10.1074/jbc.M506460200
Submitted on June 14, 2005
Revised on July 28, 2005
Accepted on August 25, 2005

Cleavage of claspin by caspase-7 during apoptosis inhibits the CHK1 pathway

Catriona A.L. Clarke, Lara N. Bennett, and Paul R. Clarke

Biomedical Research Centre, University of Dundee, Dundee DD1 9SY

Corresponding Author: paul.clarke{at}cancer.org.uk

Claspin is required for the phosphorylation and activation of Chk1 protein kinase by ATR during DNA replication and in response to DNA damage. This checkpoint pathway plays a critical role in the resistance of cells to genotoxic stress. Here, we show that human Claspin is cleaved by caspase-7 during the initiation of apoptosis. In cells, induction of DNA damage by etoposide at first produces rapid phosphorylation of Chk1 by ATR. Subsequently, etoposide causes activation of caspase-7, cleavage of Claspin, and the dephosphorylation of Chk1. In apoptotic cell extracts, Claspin is cleaved by caspase-7 at a single aspartate residue into a large amino-terminal fragment (Claspin-NTF) and a smaller carboxyl terminal fragment (Claspin-CTF) that contain different functional domains. Claspin-NTF is heavily phosphorylated in a human cell-free system in response to double stranded DNA oligonucleotides, and this fragment retains Chk1-binding activity. By contrast, Claspin-CTF does not bind Chk1, but it does associate with DNA and inhibits the DNA-dependent phosphorylation of Chk1 associated with its activation. These results indicate that cleavage of Claspin by caspase-7 inactivates the Chk1 signaling pathway. This mechanism may regulate the balance between cell cycle arrest and induction of apoptosis during the response to genotoxic stress.

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