Conservation of the Chk1 Checkpoint Pathway in Mammals: Linkage of DNA Damage to Cdk Regulation Through Cdc25
Yolanda Sanchez,
Calvin Wong,
Richard S. Thoma,
Ron Richman,
Zhiqi Wu,
Helen Piwnica-Worms,
Stephen J. Elledge
*
In response to DNA damage, mammalian cells prevent cell cycle
progression through the control of critical cell cycle regulators. A
human gene was identified that encodes the protein Chk1, a homolog of
the Schizosaccharomyces pombe Chk1 protein kinase, which is required for the DNA damage checkpoint. Human Chk1 protein was modified
in response to DNA damage. In vitro Chk1 bound to and phosphorylated the dual-specificity protein phosphatases
Cdc25A, Cdc25B, and Cdc25C, which control cell cycle transitions by
dephosphorylating cyclin-dependent kinases.
Chk1 phosphorylates Cdc25C on serine-216. As shown in an
accompanying paper by Peng et al. in this issue, serine-216
phosphorylation creates a binding site for 14-3-3 protein and inhibits function of the phosphatase. These results suggest a model
whereby in response to DNA damage, Chk1 phosphorylates and inhibits
Cdc25C, thus preventing activation of the Cdc2-cyclin B complex
and mitotic entry.
Y. Sanchez, C. Wong, S. J. Elledge, Verna and Marrs McLean
Department of Biochemistry, Department of Molecular and Human Genetics,
Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor
Plaza, Houston, TX 77030, USA.
R. S. Thoma, Z. Wu, H. Piwnica-Worms, Department of Cell Biology
and Physiology, Howard Hughes Medical Institute, Washington University
School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
R. Richman, Department of Cell Biology, Howard Hughes Medical
Institute, Baylor College of Medicine, One Baylor Plaza, Houston,
TX 77030, USA.
*
To whom correspondence should be addressed. E-mail:
selledge{at}bcm.tmc.edu
