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Chair(s): Syljuåsen, Randi
(SY008) Chk1 signaling in the G2 DNA damage checkpoint.
O'Connell, Matthew1, 1 Department of Oncological Sciences, New York, NY
ABSTRACT- Chk1 is a serine/threonine protein kinase that acts as an effector for DNA damage induced cell cycle arrest in G2. In response to DNA damage, Chk1 is phosphorylated on C-terminal residues by the ATM and ATR kinases, and this correlates with an increase in Chk1 kinase activity. Activated Chk1 maintains the mitotic CDK Cdc2 in an inactive state through modulating the activities of the kianses and phosphatases that regulate Cdc2. We have taken genetic and biochemical approaches to attempt to understand the mechanisms of Chk1 activation by phosphorylation. The data show most if not all regulation of Chk1 occurs in cis through alterations in the association of Chk1 catalytic and regualtory domains. We also show that regulation of Cdc2 activity via Chk1 is antagonized by other signaling cascades centering on the same targets, and that these pathways interact as cells progress through G2. Inactivation of Chk1 is both necessary and sufficient to overcome the checkpoint induced arrest, where PP1 activity is absolutely critical to ensure resumption of progression to mitosis.
Key words: checkpoint, chk1, cdk regulation, cell cycle
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