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Originally published as Genetics Published Articles Ahead of Print on July 2, 2006.
Genetics, Vol. 174, 113-123, September 2006, Copyright © 2006
doi:10.1534/genetics.106.060970
Antagonism of Chk1 Signaling in the G2 DNA Damage Checkpoint by Dominant Alleles of Cdr1
Teresa M. Calonge and Matthew J. O'Connell1
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029
1 Corresponding author: Mount Sinai School of Medicine, 1425 Madison Ave., Room 15-70, New York, New York 10029.
E-mail: matthew.oconnell{at}mssm.edu
Activation of the Chk1 protein kinase by DNA damage enforces a checkpoint that maintains Cdc2 in its inactive, tyrosine-15 (Y15) phosphorylated state. Chk1 downregulates the Cdc25 phosphatases and concomitantly upregulates the Wee1 kinases that control the phosphorylation of Cdc2. Overproduction of Chk1 causes G2 arrest/delay independently of DNA damage and upstream checkpoint genes. We utilized this to screen fission yeast for mutations that alter sensitivity to Chk1 signaling. We describe three dominant-negative alleles of cdr1, which render cells supersensitive to Chk1 levels, and suppress the checkpoint defects of chk1
cells. Cdr1 encodes a protein kinase previously identified as a negative regulator of Wee1 activity in response to limited nutrition, but Cdr1 has not previously been linked to checkpoint signaling. Overproduction of Cdr1 promotes checkpoint defects and exacerbates the defective response to DNA damage of cells lacking Chk1. We conclude that regulation of Wee1 by Cdr1 and possibly by related kinases is an important antagonist of Chk1 signaling and represents a novel negative regulation of cell cycle arrest promoted by this checkpoint.
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