Timeless Protein Plays a Role in Coupling Cell Cycle and Circadian Rhythms

William K. Kaufmann, Ph.D.
University of North Carolina School of Medicine
P30ES010126

Background: Circadian rhythm is the predictable "internal body clock" that regulates the 24 hour cycle of biological processes in animals and plants. Disruptions in the circadian rhythm have been implicated in a variety of diseases and conditions from common jetlag to cancer. The cell cycle is the orderly sequence of events by which a cell duplicates its contents and divides into two. These two systems have great effects on physiology at the levels of the cell, organ, and organism. While the two systems have distinct regulatory mechanisms, there is growing evidence that they are linked. Like circadian rhythms, most mammalian cells operate on an approximate 24 hour cell cycle and the circadian clock has been implicated in the regulation of the phases of cell division. This linkage is important for a new field of research and medicine known as chronotherapy, which aims to coordinate the delivery of chemotherapeutic drugs with the circadian and cell cycles to maximize drug efficacy while minimizing side effects.

In mammals, the Timeless protein is necessary for proper functioning of circadian rhythms; however, the protein is evolutionarily related to many cell cycle control proteins. Therefore, this team of NIEHS-funded investigators from the University of North Carolina set out to determine whether the Timeless protein also functions as a cell cycle or checkpoint control protein. Checkpoints are cellular pathways that are activated by environmental changes or cellular injury resulting in a protective response.

Advance: The researchers found that Timeless protein interacts with both a circadian clock protein and with cell cycle checkpoint proteins. It also appears to play a role in the DNA damage checkpoint response, which is a process that arrests cell division and activates DNA repair mechanisms. Other experiments demonstrated that inhibiting production of Timeless protein "seriously compromises" checkpoint-regulated coordination of cell division, "indicating an intimate connection between the circadian cycle and DNA damage checkpoints."

Implications: While there is still much to be learned about the function and control of Timeless protein, these results prove that it indeed acts in the control of the circadian clock and cell cycle by interacting with circadian clock proteins and playing an important role in the DNA damage response. Therefore, it is a molecular link between circadian rhythms and the cell cycle.

Citation: Unsal-Kacmaz K, Mullen TE, Kaufmann WK, Sancar A. Coupling of human circadian and cell cycles by the timeless protein. Mol Cell Biol. 2005 Apr;25(8):3109-16.