Tumor Suppression and Circadian Function

Circadian clock and cell division cycle are two fundamental biological processes. The circadian clock is the body's molecular time-keeping system, while the cell division cycle regulates development and cellular renewal. The expression of cell cycle genes such as Wee1, Cyclins, and c-Myc are under circadian control and could be directly under the regulation of the circadian transcriptional complex. This complex is composed of heterodimer transactivators CLOCK/NPAS2 with BMAL1, which regulate the transcription of PER1, PER2, CRY1, and CRY2. In turn, the repressors CRY1 and CRY2 turn off the gene expressions of Per1/Per2, Cry1/Cry2 in a periodic manner by acting on the transcriptional complex. Two of these circadian rhythm regulators, PER1 and PER2, have now been linked to DNA damage response pathways in a series of papers that examined gene dosage. Overexpression of either Per1 or Per2 in cancer cells inhibits their neoplastic growth and increases their apoptotic rate. In vivo studies showed that mice deficient in mPer2 showed significant higher incidences of tumor development after genotoxic stress. Loss and dysregulation of Per1 and Per2 gene expression have been found in many types of human cancers. Recent studies demonstrate that both PER1 and PER2 are involved in ATM-Chk1/Chk2 DNA damage response pathways and implicate normal circadian function as a factor in tumor suppression.