Beyond its role in cancer, Partch is also interested in understanding the normal role of PASD1 and why it is silencing the clock in the human germ line. The germ line is the only tissue in the body that researchers have found does not have circadian cycles.

A series of experiments in Partch's lab revealed how the protein interacts with the molecular machinery of the biological clock. There are four main clock genes, and the interactions of these genes and the proteins they encode create a feedback loop that drives molecular oscillations on a 24-hour cycle. Two proteins, CLOCK and BMAL1, form a complex that turns on the Period and Cryptochrome genes. The Period and Cryptochrome proteins then combine to turn off the genes for CLOCK and BMAL1. Partch and her colleagues found that PASD1 is structurally related to CLOCK and interferes with the function of the CLOCK-BMAL1 complex.


"It shuts the clock off very efficiently," Partch said.

The researchers also studied cancer cell lines that express PASD1 and showed that blocking the protein (using RNA interference techniques) turned the clock cycle back on in those cells. Partch's lab is continuing to investigate the biochemical mechanisms involved in the protein's interactions with the molecular clock.

"By understanding what makes the clock tick and how it is regulated, we may be able to identify points where we can intervene pharmacologically to treat disorders in which the clock is disrupted," she said.

In another recent paper from Partch's lab, published May 11 in Nature Structural & Molecular Biology, researchers at UC Santa Cruz and the University of Memphis worked out important details of the interactions between two of the main clock proteins. They found that Cryptochrome interacts with a particular section of BMAL1, and that mutations causing structural changes in that section can alter the timing of the clock, resulting in cycles as short as 19 hours or as long as 26 hours.

"This study answers the longstanding question of how Cryptochrome works, and it's something we think we can drug. If we can control this process with small molecules, we can affect the timing of the clock," Partch said.

Several clock gene mutations have been identified in people with disorders that involve the timing of the biological clock, causing either advanced sleep syndrome or delayed sleep syndrome. There is also a growing body of evidence showing that environmental changes affecting circadian rhythms, including shift work and jet lag, can have profound effects on human physiology and health.

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