Molecular Pathway to a Cellular Checkpoint

Release Date:
2/2/1998
Contact:
Doris Brody, NIGMS

For quite a few years, researchers have been racing to unravel the hundreds of molecular steps in the complex cycle of cell growth and division. They anticipate that important secrets to understanding and treating cancer and many other diseases will be found in studies of the cell cycle. The work has already been productive, shedding light on many functions of genes that are intimately associated with diseases, especially cancer. The research has also shown that the cell cycle is enormously complicated.

This year, research results from several laboratories describe the probable biochemical pathway that causes cells to stop dividing when damage to the DNA has occurred. It has been known for some time that cells contain certain "checkpoint" genes that are activated to arrest division in response to DNA damage. Such arrest allows the cell to repair the damage and prevents mutations from being passed along.

NIGMS grantees Paul Russell of the Scripps Research Institute, Helen Piwnica-Worms of the Washington University School of Medicine, and Stephen Elledge of the Baylor College of Medicine have worked out key parts of a model that explains the pathway traveled by the signals that cause cell cycle arrest after DNA damage. These researchers studied an enzyme that is essential for checkpoint activity and determined the molecule it inhibits, thus preventing activation of the central regulator that permits cell division to continue.

Understanding the specific mechanism of cell cycle arrest in response to DNA damage will help scientists target specific molecules that might be manipulated to render cancer cells more sensitive to chemotherapeutic drugs.

REFERENCES

Furnari B, Rhind N, Russell P. Cdc25 mitotic inducer targeted by Chk1 DNA damage checkpoint kinase. Science 1997;277:1495-7.

Sanchez Y, Wong C, Thoma R, Richman R, Wu Z, Piwnica-Worms H, Elledge S. Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Ccd25. Science 1997;277:1497-1501.

Peng CY, Graves P, Thoma S, Wu Z, Shaw A, Piwnica-Worms H. Mitotic and G 2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science 1997;277:1501-5.

Reporters may call the NIGMS Office of Communications and Public Liaison at (301) 496-7301 to obtain the name of a scientist in the NIGMS Division of Genetics and Developmental Biology who can comment on this work.