Antagonism of Chk1 Signaling in the G2 DNA Damage Checkpoint by Dominant Alleles of Cdr1

Activation of the Chk1 protein kinase by DNA damage enforces a checkpoint that maintains Cdc2 in its inactive, tyrosine-15 (Y15) phosphorylated state. Chk1 down-regulates the Cdc25 phosphatases and concomitantly up-regulates 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 in fission yeast for mutations that alter sensitivity to Chk1 signaling. We describe three dominant-negative alleles of cdr1, which render cells super-sensitive 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 via 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.

Key Words: Cdr1, Cell Cycle, Checkpoint, Chk1

This article has been cited by other articles:

				A. Kosoy, T. M. Calonge, E. A. Outwin, and M. J. O'Connell Fission Yeast Rnf4 Homologs Are Required for DNA Repair J. Biol. Chem., July 13, 2007; 282(28): 20388 - 20394. [Abstract] [Full Text] [PDF]

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