Coupling of Human Circadian and Cell Cycles by the Timeless Protein

Abstract

The Timeless protein is essential for circadian rhythm in Drosophila. The Timeless orthologue in mice is essential for viability and appears to be required for the maintenance of a robust circadian rhythm as well. We have found that the human Timeless protein interacts with both the circadian clock protein cryptochrome 2 and with the cell cycle checkpoint proteins Chk1 and the ATR-ATRIP complex and plays an important role in the DNA damage checkpoint response. Down-regulation of Timeless in human cells seriously compromises replication and intra-S checkpoints, indicating an intimate connection between the circadian cycle and the DNA damage checkpoints that is in part mediated by the Timeless protein.

ACKNOWLEDGMENTS

We thank P. Minoo (University of Southern California) for his generous gift of Tim antibodies. We thank C. Lee (Florida State University) for his generous gift of Per2 antibodies..

This work was supported by National Institutes of Health grants GM32833 and GM31082 (to A.S.) and CA81343 (to W.K.K.). It was also supported in part by center grants from the National Cancer Institute (P30-CA16086) and the National Institute of Environmental Health Sciences (P30-ES10126).